Benzimidazolone derivatives as bromodomain inhibitors

ABSTRACT

This application relates to chemical compounds which may act as inhibitors of, or which may otherwise modulate the activity of, a bromodomain-containing protein, including bromodomain-containing protein 4 (BRD4), and to compositions and formulations containing such compounds, and methods of using and making such compounds. Compounds include compounds of Formula (I) wherein R 1a , R 1b , R 2a , R 2b , R 3 , and X are described herein.

This application claims the benefits of U.S. Provisional Application61/805,995, filed on Mar. 28, 2013, and U.S. Provisional Application61/860,230, filed on Jul. 30, 2013, both of which are incorporatedherein by reference in their entireties.

FIELD

This application relates to chemical compounds which may inhibit orotherwise modulate the activity of a bromodomain-containing protein,including bromodomain-containing protein 4 (BRD4), and to compositionsand formulations containing such compounds, and methods of using andmaking such compounds.

BACKGROUND

The bromodomain and extraterminal (BET) family of proteins (BETproteins) are readers of the epigenetic code that couple acetylation oflysine residues on histones to changes in chromatin structure and geneexpression. The BET family includes BRD2, BRD3, BRD4, and BRDT, all ofwhich are widely expressed across diverse tissues, with the exception ofthe BRDT, whose expression is restricted to the testes. See Wu, S. Y. &Chiang, C. M., J. Biol. Chem., 282: 13141-13145 (2007). Each BET familymember contains tandem bromodomains in the N-terminal regions thatspecifically bind acelyated lysine residues in histones H3 and H4. Id.Once bound to histones, BET proteins recruit protein complexes thatmodulate gene transcription either directly, such as transcriptionalactivators or repressors, or indirectly such as chromatin remodelingcomplexes. BRD4 is the most well studied member of the BET family and isknown to preferentially recognize tetra-acelyated histone H4 epigeneticmarks. See Filippakopoulos, P., et al., Cell, 149: 214-231 (2012). BRD4recruits the p-TEFb complex to nucleosomes, which in turn phosphorylatesthe C-terminal tail of RNA polymerase II and increases thetranscriptional elongation of neighboring genes. See Yang, Z., et al.,Mol. Cell Biol., 28: 967-976 (2008); Urano, E., et al., FEBS Lett., 582:4053-4058 (2008).

The epigenetic code, including histone acetylation, is highly perturbedin many pathological disease states, resulting in the aberrantexpression of genes that control cell fate, cell differentiation, cellsurvival, and inflammatory processes. See, e.g., Cohen, I., et al.,Genes Cancer, 2: 631-647 (2011); Brooks, W. H., et al., J. Autoimmun.,34: J207-219 (2010); Wierda, R. J., et al., J. Cell Mol. Med., 14:1225-1240 (2010); Shirodkar, A. V. & Marsden, P. A., Curr. Opin.Cardiol., 26: 209-215 (2011); Villeneuve, L. M., et al., Clin. Exp.Pharmacol. Physiol., 38: 401-409 (2011). BET proteins including BRD4have been identified as important mediators of altered gene expressionprofiles found in numerous diseases including cancer, diabetes, obesity,atherosclerosis, cardiovascular and renal disorders, and viralinfection. See Muller, S., et al., Expert Rev. Mol. Med., 13: e29(2011); Zhou, M., et al., J. Virol., 83: 1036-1044 (2009); Chung, C. W.,et al., J. Med. Chem., 54: 3827-3838 (2011). For example, MYC has beenimplicated in the majority of human cancers and BET proteins have beenidentified as regulatory factors of c-Myc; inhibition of BET, includingBRD4, has been shown to downregulate MYC transcription. See Delmore, J.E., et al. Cell, 146, 904-17 (2011); Lovén, J. et al., Cell, 153, 320-34(2013) Inhibitors and modulators of BET proteins, including BRD4, aretherefore needed.

SUMMARY

One aspect provides for a compound of Formula (I)

wherein

-   -   R^(1a) and R^(1b) are each independently C₁-C₆ alkyl, C₁-C₆        alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, C₁-C₆ hydroxyalkyl,        C₃-C₆ cycloalkyl, or CH₂—C₃-C₆ cycloalkyl;    -   R^(2a) and R^(2b) are each independently H or halogen;    -   R³ is        -   C₅-C₁₀ aryl, C₅-C₁₀ heteroaryl, or C₅-C₁₀ heteroarylalkyl,            each of which is optionally substituted with from 1 to 5 R²⁰            groups; or        -   —S(O)₂NHR⁴,            -   wherein R⁴ is C₁-C₆ alkyl or C₃-C₇ cycloalkyl, each of                which is optionally substituted with from 1 to 5 R²⁰                groups; or        -   a moiety of the formula

-   -   wherein        -   R⁶ is H, OH, or halogen; and R⁷ and R⁸ are each            independently C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,            C₃-C₆ cycloalkyl, C₁-C₆ heteroalkyl, C₅-C₁₂ aryl, C₅-C₁₂            heteroaryl, or C₅-C₁₂ heteroarylalkyl, each of which is            optionally substituted with from 1 to 5 R²⁰ groups; or R⁶ is            H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆            cycloalkyl, phenyl, naphthyl, or C₃-C₁₂ heteroaryl; and R⁷            and R⁸ together form a C₁-C₆ alkylidene group having a            double bond with the carbon to which each of            -   R⁶, R⁷, and R⁸ are bound wherein each of the C₁-C₆                alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, —C₃-C₆ cycloalkyl,                phenyl, naphthyl, or C₃-C₁₂ heteroaryl groups is                optionally substituted with from 1 to 5 R²⁰ groups;    -   X is N-Q, or O;    -   Q is H, C₁-C₃ alkyl, C₁-C₃ haloalkyl, benzyl or substituted        benzyl;    -   each R²⁰ is independently C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₁-C₆        heteroalkyl, C₃-C₆ heterocyclic, C₅-C₁₂ aryl, C₅-C₁₂ heteroaryl,        halogen, oxo, —OR^(a), —C(O)R^(a), —C(O)OR^(a),        —C(O)NR^(a)R^(b), —OC(O)NR^(a)R^(b), —NR^(a)R^(b),        —NR^(a)C(O)R^(b), —NR^(a)C(O)OR^(b), —S(O)₀₋₂R^(a),        —S(O)₂NR^(a)R^(b), —NR^(a)S(O)₂R^(b), —N₃, —CN, or —NO₂, wherein        each C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₁-C₆ heteroalkyl, C₃-C₆        heterocyclic, C₅-C₁₂ aryl, C₅-C₁₂ heteroaryl is optionally        substituted with from one to five halogen, oxo, —OR^(a),        —C(O)R^(a), —C(O)OR^(a), —C(O)NR^(a)R^(b), —OC(O)NR^(a)R^(b),        —NR^(a)R^(b), —NR^(a)C(O)R^(b), —NR^(a)C(O)OR^(b),        —S(O)₀₋₂R^(a), —S(O)₂NR^(a)R^(b), —NR^(a)S(O)₂R^(b), —N₃, —CN,        or —NO₂;    -   each R^(a) and R^(b) is independently H; or C₁-C₆ alkyl, C₃-C₆        cycloalkyl, C₁-C₆ heteroalkyl, C₃-C₆ heterocyclic, C₅-C₁₂ aryl,        C₅-C₁₂ heteroaryl, each of which is optionally substituted with        from one to five R²¹; or R^(a) and R^(b) together with the atoms        to which they are attached form a heterocycle, and;    -   each R²¹ is independently C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₁-C₆        heteroalkyl, C₃-C₆ heterocyclic, C₅-C₁₂ aryl, C₅-C₁₂ heteroaryl,        or halogen;

or a pharmaceutically acceptable salt thereof.

Another aspect provides for a compound selected from the groupconsisting the title compounds listed in Examples 1 to 201.

Another aspect provides for a pharmaceutical composition comprising acompound of Formula (I), or a pharmaceutically acceptable salt thereof,and a pharmaceutically acceptable carrier.

Another aspect provides for a use of a compound of Formula (I), or apharmaceutically acceptable salt thereof, in therapy. Such aspectsinclude use of a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, for the treatment of a subject having a diseaseor condition responsive to the inhibition of a bromodomain-containingprotein; and use of a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, for the manufacture of a medicament for thetreatment of a human having a disease or condition responsive to theinhibition of a bromodomain-containing protein. Another aspect providesfor a method of treating a subject having a disease or conditionresponsive to the inhibition of a bromodomain-containing protein,comprising administering a therapeutically effective amount of acompound of Formula (I), or a pharmaceutically acceptable salt thereof.In some aspects, the bromodomain-containing protein is BRD4. In someaspects, the disease or condition is an autoimmune disease, aninflammatory disease, a neurodegenerative disease, a cancer, acardiovascular disorder, a renal disorder, a viral infection, orobesity. In certain embodiments, the disease or condition is chosen fromrheumatoid arthritis, osteoarthritis, atherosclerosis, psoriasis,systemic lupus erythematosus, multiple sclerosis, inflammatory boweldisease, asthma, chronic obstructive airways disease, pneumonitis,dermatitis, alopecia, nephritis, vasculitis, atherosclerosis,Alzheimer's disease, hepatitis, primary biliary cirrhosis, sclerosingcholangitis, diabetes (including type I diabetes), acute rejection oftransplanted organs, lymphomas, multiple myelomas, leukemias, neoplasmsand solid tumors. In some aspects the disease or condition is a solidtumor of the colon, rectum, prostate, lung, pancreas, liver, kidney,cervix, stomach, ovaries, breast, skin, brain, meninges, or centralnervous system (including a neuroblastoma or a glioblastoma). In someaspects, the disease or condition is a lymphoma. In some aspects, thedisease or condition is a B-cell lymphoma. In some aspects, the diseaseor condition is Burkitt's lymphoma. In some aspects, the disease orcondition is diffuse large B-cell lymphoma. In some aspects, the diseaseor condition is multiple myeloma. In some aspects the disease orcondition is a carcinoma. In some aspects the disease or condition isNUT midline cardinoma. In some aspects the subject is a human.

Another aspect provides for a method of downregulating or decreasing MYCtranscription in a subject, comprising administering to the subject acompound of Formula (I). Another aspect provides for a method oftreating a disease or condition in a subject in which activation of MYCis implicated, comprising administering to the subject a compound ofFormula (I).

In some aspects, the compound is administered intravenously,intramuscularly, parenterally, nasally, or orally. In one aspect, thecompound is administered orally.

Also provided is a method of inhibiting a bromodomain in a subject,comprising providing to the subject a therapeutically effective amountof a compound of Formula (I) or a pharmaceutically or a pharmaceuticallyacceptable salt thereof acceptable salt thereof. Also provided is amethod of inhibiting a bromodomain in a cell, comprising providing tothe cell a compound of Formula (I). It is understood that providing tothe cell may be accomplished by administering the compound to thesubject. Also provided is a method of inhibiting a bromodomain,comprising contacting the bromodomain with a compound of Formula (I), ora pharmaceutically acceptable salt thereof.

Also provided is the use of a compound of Formula (I), or apharmaceutically acceptable salt thereof, in the manufacture of amedicament for the treatment of a disease or condition responsive tobromodomain inhibition.

Also provided are kits that include a compound of Formula (I), or apharmaceutically acceptable salt thereof. In one aspect, the kit furtherincludes instructions for use. In one aspect, a kit includes a compoundof Formula (I), or a pharmaceutically acceptable salt thereof, andinstructions for use of the compounds in the treatment of the diseasesor conditions described above.

Also provided are articles of manufacture that include a compound ofFormula (I), or a pharmaceutically acceptable salt thereof. In oneembodiment, the container may be a vial, jar, ampoule, preloadedsyringe, or an intravenous bag.

DETAILED DESCRIPTION

Described herein are compounds of Formula (I), which include compoundsof Formulae (Ia) and (Ib), compositions and formulations containing suchcompounds, and methods of using and making such compounds.

One aspect of the current disclosure relates to compounds of Formula (I)

wherein

-   -   R^(1a) and R^(1b) are each independently C₁-C₆ alkyl, C₁-C₆        alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, C₁-C₆ hydroxyalkyl,        C₃-C₆ cycloalkyl, or CH₂—C₃-C₆ cycloalkyl;    -   R^(2a) and R^(2b) are each independently H or halogen;    -   R³ is        -   C₅-C₁₀ aryl, C₅-C₁₀ heteroaryl, or C₅-C₁₀ heteroarylalkyl,            each of which is optionally substituted with from 1 to 5 R²⁰            groups; or        -   —S(O)₂NHR⁴,            -   wherein R⁴ is C₁-C₆ alkyl or C₃-C₇ cycloalkyl, each of                which is optionally substituted with from 1 to 5 R²⁰                groups; or        -   a moiety of the formula

-   -   wherein        -   R⁶ is H, OH, or halogen; and R⁷ and R⁸ are each            independently C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,            C₃-C₆ cycloalkyl, C₁-C₆ heteroalkyl, C₅-C₁₂ aryl, C₅-C₁₂            heteroaryl, or C₅-C₁₂ heteroarylalkyl, each of which is            optionally substituted with from 1 to 5 R²⁰ groups; or            -   R⁶ is H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,                C₃-C₆ cycloalkyl, phenyl, naphthyl, or C₃-C₁₂                heteroaryl; and R⁷ and R⁸ together form a C₁-C₆                alkylidene group having a double bond with the carbon to                which each of R⁶, R⁷, and R⁸ are bound wherein each of                the C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, —C₃-C₆                cycloalkyl, phenyl, naphthyl, or C₃-C₁₂ heteroaryl                groups is optionally substituted with from 1 to 5 R²⁰                groups;    -   X is N-Q, or O;    -   Q is H, C₁-C₃ alkyl, C₁-C₃ haloalkyl, benzyl or substituted        benzyl;    -   each R²⁰ is independently C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₁-C₆        heteroalkyl, C₃-C₆ heterocyclic, C₅-C₁₂ aryl, C₅-C₁₂ heteroaryl,        halogen, oxo, —OR^(a), —C(O)R^(a), —C(O)OR^(a),        —C(O)NR^(a)R^(b), —OC(O)NR^(a)R^(b), —NR^(a)R^(b),        —NR^(a)C(O)R^(b), —NR^(a)C(O)OR^(b), —S(O)₀₋₂R^(a),        —S(O)₂NR^(a)R^(b), —NR^(a)S(O)₂R^(b), —N₃, —CN, or —NO₂, wherein        each C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₁-C₆ heteroalkyl, C₃-C₆        heterocyclic, C₅-C₁₂ aryl, C₅-C₁₂ heteroaryl is optionally        substituted with from one to five halogen, oxo, —OR^(a),        —C(O)R^(a), —C(O)OR^(a), —C(O)NR^(a)R^(b), —OC(O)NR^(a)R^(b),        —NR^(a)R^(b), —NR^(a)C(O)R^(b), —NR^(a)C(O)OR^(b), —S(O)₀₋₂R,        —S(O)₂NR^(a)R^(b), —NR^(a)S(O)₂R^(b), —N₃, —CN, or —NO₂;    -   each R^(a) and R^(b) is independently H; or C₁-C₆ alkyl, C₃-C₆        cycloalkyl, C₁-C₆ heteroalkyl, C₃-C₆ heterocyclic, C₅-C₁₂ aryl,        C₅-C₁₂ heteroaryl, each of which is optionally substituted with        from one to five R²¹; or R^(a) and R^(b) together with the atoms        to which they are attached form a heterocycle, and;    -   each R²¹ is independently C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₁-C₆        heteroalkyl, C₃-C₆ heterocyclic, C₅-C₁₂ aryl, C₅-C₁₂ heteroaryl,        or halogen;

or a pharmaceutically acceptable salt thereof.

One subset of compounds of Formula (I) relates to compounds of Formula(Ia)

wherein

-   -   R³ is        -   C₅-C₁₀ aryl, C₅-C₁₀ heteroaryl, or C₅-C₁₀ heteroarylalkyl,            each of which is optionally substituted with from 1 to 5 R²⁰            groups; or        -   —S(O)₂NHR⁴,            -   wherein R⁴ is C₁-C₆ alkyl or C₃-C₇ cycloalkyl, each of                which is optionally substituted with from 1 to 5 R²⁰                groups; or        -   a moiety of the formula

-   -   wherein        -   R⁶ is H, OH, or halogen; and R⁷ and R⁸ are each            independently C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,            C₃-C₆ cycloalkyl, C₁-C₆ heteroalkyl, C₅-C₁₂ aryl, C₅-C₁₂            heteroaryl, or C₅-C₁₂ heteroarylalkyl, each of which is            optionally substituted with from 1 to 5 R²⁰ groups; or            -   R⁶ is H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,                C₃-C₆ cycloalkyl, phenyl, naphthyl, or C₃-C₁₂                heteroaryl; and R⁷ and R⁸ together form a C₁-C₆                alkylidene group having a double bond with the carbon to                which each of R⁶, R⁷, and R⁸ are bound wherein each of                the C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, —C₃-C₆                cycloalkyl, phenyl, naphthyl, or C₃-C₁₂ heteroaryl                groups is optionally substituted with from 1 to 5 R²⁰                groups;    -   Q is H, C₁-C₃ alkyl, C₁-C₃ haloalkyl, benzyl or substituted        benzyl;    -   each R²⁰ is independently C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₁-C₆        heteroalkyl, C₃-C₆ heterocyclic, C₅-C₁₂ aryl, C₅-C₁₂ heteroaryl,        halogen, oxo, —OR^(a), —C(O)R^(a), —C(O)OR^(a),        —C(O)NR^(a)R^(b), —OC(O)NR^(a)R^(b), —NR^(a)R^(b),        —NR^(a)C(O)R^(b), —NR^(a)C(O)OR^(b), —S(O)₀₋₂R^(a),        —S(O)₂NR^(a)R^(b), —NR^(a)S(O)₂R^(b), —N₃, —CN, or —NO₂, wherein        each C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₁-C₆ heteroalkyl, C₃-C₆        heterocyclic, C₅-C₁₂ aryl, C₅-C₁₂ heteroaryl is optionally        substituted with from one to five halogen, oxo, —OR^(a),        —C(O)R^(a), —C(O)OR^(a), —C(O)NR^(a)R^(b), —OC(O)NR^(a)R^(b),        —NR^(a)R^(b), —NR^(a)C(O)R^(b), —NR^(a)C(O)OR^(b),        —S(O)₀₋₂R^(a), —S(O)₂NR^(a)R^(b), —NR^(a)S(O)₂R^(b), —N₃, —CN,        or —NO₂;    -   each R^(a) and R^(b) is independently H; or C₁-C₆ alkyl, C₃-C₆        cycloalkyl, C₁-C₆ heteroalkyl, C₃-C₆ heterocyclic, C₅-C₁₂ aryl,        C₅-C₁₂ heteroaryl, each of which is optionally substituted with        from one to five R²¹; or R^(a) and R^(b) together with the atoms        to which they are attached form a heterocycle, and;    -   each R²¹ is independently C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₁-C₆        heteroalkyl, C₃-C₆ heterocyclic, C₅-C₁₂ aryl, C₅-C₁₂ heteroaryl,        or halogen;

or a pharmaceutically acceptable salt thereof.

Another subset of compounds of Formula (I) relates to compounds ofFormula (Ib)

wherein

-   -   R³ is        -   C₅-C₁₀ aryl, C₅-C₁₀ heteroaryl, or C₅-C₁₀ heteroarylalkyl,            each of which is optionally substituted with from 1 to 5 R²⁰            groups; or        -   —S(O)₂NHR⁴,            -   wherein R⁴ is C₁-C₆ alkyl or C₃-C₇ cycloalkyl, each of                which is optionally substituted with from 1 to 5 R²⁰                groups; or        -   a moiety of the formula

-   -   wherein        -   R⁶ is H, OH, or halogen; and R⁷ and R⁸ are each            independently C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,            C₃-C₆ cycloalkyl, C₁-C₆ heteroalkyl, C₅-C₁₂ aryl, C₅-C₁₂            heteroaryl, or C₅-C₁₂ heteroarylalkyl, each of which is            optionally substituted with from 1 to 5 R²⁰ groups; or            -   R⁶ is H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,                C₃-C₆ cycloalkyl, phenyl, naphthyl, or C₃-C₁₂                heteroaryl; and R⁷ and R⁸ together form a C₁-C₆                alkylidene group having a double bond with the carbon to                which each of R⁶, R⁷, and R⁸ are bound wherein each of                the C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, —C₃-C₆                cycloalkyl, phenyl, naphthyl, or C₃-C₁₂ heteroaryl                groups is optionally substituted with from 1 to 5 R²⁰                groups;    -   each R²⁰ is independently C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₁-C₆        heteroalkyl, C₃-C₆ heterocyclic, C₅-C₁₂ aryl, C₅-C₁₂ heteroaryl,        halogen, oxo, —OR^(a), —C(O)R^(a), —C(O)OR^(a),        —C(O)NR^(a)R^(b), —OC(O)NR^(a)R^(b), —NR^(a)R^(b),        —NR^(a)C(O)R^(b), —NR^(a)C(O)OR^(b), —S(O)₀₋₂R^(a),        —S(O)₂NR^(a)R^(b), —NR^(a)S(O)₂R^(b), —N₃, —CN, or —NO₂, wherein        each C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₁-C₆ heteroalkyl, C₃-C₆        heterocyclic, C₅-C₁₂ aryl, C₅-C₁₂ heteroaryl is optionally        substituted with from one to five halogen, oxo, —OR^(a),        —C(O)R^(a), —C(O)OR^(a), —C(O)NR^(a)R^(b), —OC(O)NR^(a)R^(b),        —NR^(a)R^(b), —NR^(a)C(O)R^(b), —NR^(a)C(O)OR^(b),        —S(O)₀₋₂R^(a), —S(O)₂NR^(a)R^(b), —NR^(a)S(O)₂R^(b), —N₃, —CN,        or —NO₂;    -   each R^(a) and R^(b) is independently H; or C₁-C₆ alkyl, C₃-C₆        cycloalkyl, C₁-C₆ heteroalkyl, C₃-C₆ heterocyclic, C₅-C₁₂ aryl,        C₅-C₁₂ heteroaryl, each of which is optionally substituted with        from one to five R²¹; or R^(a) and R^(b) together with the atoms        to which they are attached form a heterocycle, and;    -   each R²¹ is independently C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₁-C₆        heteroalkyl, C₃-C₆ heterocyclic, C₅-C₁₂ aryl, C₅-C₁₂ heteroaryl,        or halogen;

or a pharmaceutically acceptable salt thereof.

In some compounds of Formula (I), R^(1a) and R^(1b) are eachindependently C₁-C₆ alkyl. In some compounds of Formula (I), R^(1a) andR^(1b) are each independently methyl, ethyl, or propyl. In somecompounds of Formula (I), R^(1a) and R^(1b) are different. In somecompounds of Formula (I), R^(1a) and R^(1b) are the same. In somecompounds of Formula (I), R^(1a) and R^(1b) are both methyl.

In some compounds of Formula (I), R^(2a) and R^(2b) are both H. In somecompounds of Formula (I), R^(2a) and R^(2b) are both halo. In somecompounds of Formula (I), one of R^(2a) and R^(2b) is H and the other ishalo. In some compounds of Formula (I), the halo is —F or —Cl.

In some compound of Formula (I), X is N-Q.

In some compounds of Formula (I) or (Ia), Q is H, C₁-C₃ alkyl, or C₁-C₃haloalkyl.

In some compounds of Formula (I), (Ia) or (Ib), R³ is C₅-C₁₀ aryl,C₅-C₁₀ heteroaryl, or C₅-C₁₀ heteroarylalkyl, each of which isoptionally substituted with from 1 to 5 R²⁰ groups.

In some compounds of Formula (I), (Ia) or (Ib), R³ is phenyl, oxetanyl,tetrahydrofuranyl, furanyl, tetrahydrothiophenyl, thiophenyl, pyrrolyl,pyrrolinyl, pyrrolidinyl, dioxolanayl, oxazolyl, thiazolyl, imidazolyl,imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl,isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyranyl,pyridinyl, piperidinyl, dioxanyl, morpholinyl, thiomorpholinyl,pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, triazinyl,indolizinyl, indolyl, isoindolyl, indolinyl, chromenyl, benzofuranyl,benzothiophenyl, dihydrobenzothiophenyl, indazolyl, benzimidazolyl,benzothiazolyl, benzoxazolyl, imidazo[1,2-a]pyridinyl, purinyl,quinolinyl, quinolizinyl, isoquinolinyl, cinnolinyl, phthalazinyl,quinazolinyl, quinoxalinyl, indenyl, naphthalenyl, or azulenyl, each ofwhich is optionally substituted with from 1 to 5 R²⁰ groups.

In some compounds of Formula (I), (Ia) or (Ib), R³ is a moiety of theformula

wherein R⁶ is H, OH, or halogen; and R⁷ and R⁸ are each independentlyC₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₁-C₆heteroalkyl, C₅-C₁₂ aryl, C₅-C₁₂ heteroaryl, or C₅-C₁₂ heteroarylalkyl,each of which is optionally substituted with from 1 to 5 R²⁰ groups. Insome compounds, R⁶ is OH. In some compounds, R⁷ and R⁸ are eachindependently C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₁-C₆ heteroalkyl, C₅-C₁₂aryl, C₅-C₁₂ heteroaryl, or C₅-C₁₂ heteroarylalkyl, each of which isoptionally substituted with from 1 to 5 R²⁰ groups. In some compounds ofFormula (I), (Ia) or (Ib), R⁷ and R⁸ are each independently C₁-C₆ alkyl,C₆ aryl or C₆ heteroaryl, each of which is optionally substituted withfrom 1 to 5 R²⁰ groups. In some compounds, R⁷ and R⁸ are eachindependently C₆ aryl or C₆ heteroaryl (e.g. a pyridyl), each of whichis optionally substituted with from 1 to 5 R²⁰ groups. In some compoundsof Formula (I), (Ia) or (Ib), R⁷ and R⁸ are each independently C₁-C₆alkyl, each of which is optionally substituted with from 1 to 5 R²⁰groups.

Other non-limiting examples of R³ include the following:

Additional non-limiting examples of R³ include the following:

In another aspect, the compound of Formula (I) may be any of thefollowing compounds:

In another aspect, the compound of Formula (I) may be any of thefollowing compounds:

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art. It must be noted that as used herein and in the appendedclaims, the singular forms “a”, “and”, and “the” include pluralreferents unless the context clearly dictates otherwise. Thus, e.g.,reference to “the compound” includes a plurality of such compounds andreference to “the assay” includes reference to one or more assays andequivalents thereof known to those skilled in the art, and so forth.

A dash at the front or end of a chemical group is a matter ofconvenience; chemical groups may be depicted with or without one or moredashes without losing their ordinary meaning. A wavy line drawn througha line in a structure indicates a point of attachment of a group. Adashed line indicates an optional bond. Unless chemically orstructurally required, no directionality is indicated or implied by theorder in which a chemical group is written. For instance, the group“—SO₂CH₂—” is equivalent to “—CH₂SO₂—” and both may be connected ineither direction. The prefix “C_(u-v)” indicates that the followinggroup has from u to v carbon atoms, one or more of which, in certaingroups (e.g. heteroalkyl, heteroaryl, heteroarylalkyl, etc.), may bereplaced with one or more heteroatoms or heteroatomic groups. Forexample, “C₁-6 alkyl” indicates that the alkyl group has from 1 to 6carbon atoms.

Also, certain commonly used alternative chemical names may or may not beused. For example, a divalent group such as a divalent “alkyl” group, adivalent “aryl” group, etc., may also be referred to as an “alkylene”group or an “alkylenyl” group, an “arylene” group or an “arylenyl”group, respectively.

“Alkyl” refers to any group derived from a linear or branched saturatedhydrocarbon. Alkyl groups include, but are not limited to, methyl,ethyl, propyls such as propan-1-yl, propan-2-yl (iso-propyl), butylssuch as butan-1-yl, butan-2-yl (sec-butyl), 2-methyl-propan-1-yl(iso-butyl), 2-methyl-propan-2-yl (t-butyl), pentyls, hexyls, octyls,decyls, and the like. Unless otherwise specified, an alkyl group hasfrom 1 to about 10 carbon atoms, for example from 1 to 10 carbon atoms,for example from 1 to 6 carbon atoms, for example from 1 to 4 carbonatoms.

“Alkenyl” refers to any group derived from a straight or branchedhydrocarbon with at least one carbon-carbon double bond. Alkenyl groupsinclude, but are not limited to, ethenyl (vinyl), propenyl (allyl),1-butenyl, 1,3-butadienyl, and the like. Unless otherwise specified, analkenyl group has from 2 to about 10 carbon atoms, for example from 2 to10 carbon atoms, for example from 2 to 6 carbon atoms, for example from2 to 4 carbon atoms.

“Alkynyl” refers to any group derived from a straight or branchedhydrocarbon with at least one carbon-carbon triple bond and includesthose groups having one triple bond and one double bond. Examples ofalkynyl groups include, but are not limited to, ethynyl (—C≡CH),propargyl (—CH₂C≡CH), (E)-pent-3-en-1-ynyl, and the like. Unlessotherwise specified, an alkynyl group has from 2 to about 10 carbonatoms, for example from 2 to 10 carbon atoms, for example from 2 to 6carbon atoms, for example from 2 to 4 carbon atoms.

“Aryl” refers to any group derived from one or more aromatic rings, thatis, a single aromatic ring, a bicyclic or a multicyclic ring system.Aryl groups include, but are not limited to, those groups derived fromacenaphthylene, anthracene, azulene, benzene, chrysene, acyclopentadienyl anion, naphthalene, fluoranthene, fluorene, indane,perylene, phenalene, phenanthrene, pyrene and the like.

“Arylalkyl” (also “aralkyl”) refers to any combination of one or morearyl groups and one or more alkyl groups. Arylalkyl groups include, butare not limited to, those groups derived from benzyl, tolyl,dimethylphenyl, 2-phenylethan-1-yl, 2-naphthylmethyl,phenylmethylbenzyl, 1,2,3,4-tetrahydronapthyl, and the like. Anarylalkyl group comprises from 6 to about 30 carbon atoms, for examplethe alkyl group can comprise from 1 to about 10 carbon atoms and thearyl group can comprise from 5 to about 20 carbon atoms.

“Cycloalkyl” refers to a cyclic alkyl group. A cycloalkyl group can haveone or more cyclic rings and includes fused and bridged groups. Examplesinclude, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, adamantyl, methylcycloproyl (cyclopropylmethyl),ethylcyclopropyl, and the like.

“Halo” and “halogen” refer to fluoro, chloro, bromo and iodo.

“Haloalkyl” refers to an alkyl wherein one or more hydrogen atoms areeach replaced by a halogen. Examples include, but are not limited to,—CH₂Cl, —CH₂F, —CH₂Br, —CFClBr, —CH₂CH₂Cl, —CH₂CH₂F, —CF₃, —CH₂CF₃,—CH₂CCl₃, and the like, as well as alkyl groups such as perfluoroalkylin which all hydrogen atoms are replaced by fluorine atoms.

“Heteroalkyl” refers to an alkyl in which one or more of the carbonatoms (and any associated hydrogen atoms) are each independentlyreplaced with the same or different heteroatom or heteroatomic group.Heteroatoms include, but are not limited to, N, P, O, S, etc.Heteroatomic groups include, but are not limited to, —NR—, —O—, —S—,—PH—, —P(O)₂—, —S(O)—, —S(O)₂—, and the like, where R is H, alkyl, aryl,cycloalkyl, heteroalkyl, heteroaryl or cycloheteroalkyl. The term“heteroalkyl” includes heterocycloalkyl (a cyclic heteroalkyl group),alkyl-heterocycloalkyl (a linear or branched C1-C6 alkyl group attachedto a cyclic heteroalkyl group), and the like. Heteroalkyl groupsinclude, but are not limited to, —OCH₃, —CH₂OCH₃, —SCH₃, —CH₂SCH₃,—NRCH₃, —CH₂NRCH₃, and the like, where R is hydrogen, alkyl, aryl,arylalkyl, heteroalkyl, or heteroaryl, each of which may be optionallysubstituted. A heteroalkyl group comprises from 1 to about 10 carbon andhetero atoms, e.g., from 1 to 6 carbon and hetero atoms.

“Heteroaryl” refers to an aryl group in which one or more of the carbonatoms (and any associated hydrogen atoms) are each independentlyreplaced with the same or different heteroatom or heteroatomic group, asdefined above. Heteroaryl groups include, but are not limited to, groupsderived from acridine, benzoimidazole, benzothiophene, benzofuran,benzoxazole, benzothiazole, carbazole, carboline, cinnoline, furan,imidazole, imidazopyridine, indazole, indole, indoline, indolizine,isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline,isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine,phenanthridine, phenanthroline, phenazine, phthalazine, pteridine,purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine,pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline,tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene, and thelike.

“Heteroarylalkyl” refers to an arylalkyl group in which one or morecarbon atoms (and any associated hydrogen atoms) are independentlyreplaced with the same or different heteroatoms or heteratomic groups,as defined above. Heteroarylalkyl groups include, but are not limitedto, groups derived from heteroaryl groups with alkyl substituents (e.g.methylpyridines, ethylthiophenes, methylthiazoles, dimethylisoxazoles,etc.), hydrogenated heteroaryl groups (dihydroquinolines, e.g.3,4-dihydroquinoline, dihydroisoquinolines, e.g.1,2-dihydroisoquinoline, dihydroimidazole, tetrahydroimidazole, etc.),indoline, isoindoline, isoindolones (e.g. isoindolin-1-one), isatin,dihydrophthalazine, quinolinone,spiro[cyclopropane-1,1′-isoindolin]-3′-one, and the like.

“Heterocycle,” “heterocyclic,” and “heterocyclyl” refer to a singlesaturated or partially unsaturated non-aromatic ring or a non-aromaticmultiple-ring system with at least one heteroatom or heteroatomic group,as defined above. Heterocycles include, but are not limited to, groupsderived from azetidine, aziridine, imidazolidine, morpholine, oxirane(epoxide), oxetane, piperazine, piperidine, pyrazolidine, piperidine,pyrrolidine, pyrrolidinone, tetrahydrofuran, tetrahydrothiophene,dihydropyridine, tetrahydropyridine, quinuclidine, N-bromopyrrolidine,N-chloropiperidine, and the like.

The term “pharmaceutically acceptable” with respect to a substancerefers to that substance which is generally regarded as safe andsuitable for use without undue toxicity, irritation, allergic response,and the like, commensurate with a reasonable benefit/risk ratio.

“Pharmaceutically acceptable salt” refers to a salt of a compound thatis pharmaceutically acceptable and that possesses (or can be convertedto a form that possesses) the desired pharmacological activity of theparent compound. Such salts include acid addition salts formed withinorganic acids such as hydrochloric acid, hydrobromic acid, sulfuricacid, nitric acid, phosphoric acid, and the like; or formed with organicacids such as acetic acid, benzenesulfonic acid, benzoic acid,camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid,glucoheptonic acid, gluconic acid, lactic acid, maleic acid, malonicacid, mandelic acid, methanesulfonic acid, 2-napththalenesulfonic acid,oleic acid, palmitic acid, propionic acid, stearic acid, succinic acid,tartaric acid, p-toluenesulfonic acid, trimethylacetic acid, and thelike, and salts formed when an acidic proton present in the parentcompound is replaced by either a metal ion, e.g., an alkali metal ion,an alkaline earth ion, or an aluminum ion; or coordinates with anorganic base such as diethanolamine, triethanolamine, N-methylglucamineand the like. Also included in this definition are ammonium andsubstituted or quaternized ammonium salts. Representative non-limitinglists of pharmaceutically acceptable salts can be found in S. M. Bergeet al., J. Pharma Sci., 66(1), 1-19 (1977), and Remington: The Scienceand Practice of Pharmacy, R. Hendrickson, ed., 21st edition, Lippincott,Williams & Wilkins, Philadelphia, Pa., (2005), at p. 732, Table 38-5,both of which are hereby incorporated by reference herein.

“Subject” and “subjects” refers to humans, domestic animals (e.g., dogsand cats), farm animals (e.g., cattle, horses, sheep, goats and pigs),laboratory animals (e.g., mice, rats, hamsters, guinea pigs, pigs,rabbits, dogs, and monkeys), and the like.

“Treating” and “treatment” of a disease include the following:

-   -   (1) preventing or reducing the risk of developing the disease,        i.e., causing the clinical symptoms of the disease not to        develop in a subject that may be exposed to or predisposed to        the disease but does not yet experience or display symptoms of        the disease,    -   (2) inhibiting the disease, i.e., arresting or reducing the        development of the disease or its clinical symptoms, or    -   (3) relieving the disease, i.e., causing regression of the        disease or its clinical symptoms.

“Effective amount” refers to an amount that may be effective to elicitthe desired biological, clinical, or medical response, including theamount of a compound that, when administered to a subject for treating adisease, is sufficient to effect such treatment. The effective amountwill vary depending on the compound, the disease and its severity andthe age, weight, etc., of the subject to be treated. The effectiveamount can include a range of amounts.

It it understood that combinations of chemical groups may be used andwill be recognized by persons of ordinary skill in the art. Forinstance, the group “hydroxyalkyl” would refer to a hydroxyl groupattached to an alkyl group. A great number of such combinations may bereadily envisaged.

Provided are also compounds in which from 1 to n hydrogen atoms attachedto a carbon atom may be replaced by a deuterium atom or D, in which n isthe number of hydrogen atoms in the molecule. As known in the art, thedeuterium atom is a non-radioactive isotope of the hydrogen atom. Suchcompounds exhibit may increase resistance to metabolism, and thus may beuseful for increasing the half-life of the compounds when administeredto a mammal. See, e.g., Foster, “Deuterium Isotope Effects in Studies ofDrug Metabolism,” Trends Pharmacol. Sci., 5(12):524-527 (1984). Suchcompounds are synthesized by means well known in the art, for example byemploying starting materials in which one or more hydrogen atoms havebeen replaced by deuterium.

Compounds of a given formula described herein encompasses the compounddisclosed and all pharmaceutically acceptable salts, stereoisomers,tautomers, solvates, and deuterated forms thereof, unless otherwisespecified.

The pharmaceutical compositions of compounds of Formula (I) (includingcompounds of Formulae (Ia) and (Ib)) may be administered in eithersingle or multiple doses by any of the accepted modes of administrationof agents having similar utilities, for example as described in thosepatents and patent applications incorporated by reference, includingrectal, buccal, intranasal and transdermal routes, by intra-arterialinjection, intravenously, intraperitoneally, parenterally,intramuscularly, subcutaneously, orally, topically, as an inhalant, orvia an impregnated or coated device such as a stent, for example, or anartery-inserted cylindrical polymer.

In one aspect, the compounds described herein may be administeredorally. Oral administration may be via, for example, capsule or entericcoated tablets. In making the pharmaceutical compositions that includeat least one compound of Formula (I), or a pharmaceutically acceptablesalt, ester, prodrug, or solvate thereof, the active ingredient isusually diluted by an excipient and/or enclosed within such a carrierthat can be in the form of a capsule, sachet, paper or other container.When the excipient serves as a diluent, it can be in the form of asolid, semi-solid, or liquid material (as above), which acts as avehicle, carrier or medium for the active ingredient. Thus, thecompositions can be in the form of tablets, pills, powders, lozenges,sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups,aerosols (as a solid or in a liquid medium), ointments containing, forexample, up to 10% by weight of the active compound, soft and hardgelatin capsules, sterile injectable solutions, and sterile packagedpowders.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose. The formulations can additionally include: lubricating agentssuch as talc, magnesium stearate, and mineral oil; wetting agents;emulsifying and suspending agents; preserving agents such as methyl andpropylhydroxy-benzoates; sweetening agents; and flavoring agents.

The compositions that include at least one compound of Formula (I), or apharmaceutically acceptable salt, ester, prodrug, or solvate thereof,can be formulated so as to provide quick, sustained or delayed releaseof the active ingredient after administration to the subject byemploying procedures known in the art. Controlled release drug deliverysystems for oral administration include osmotic pump systems anddissolutional systems containing polymer-coated reservoirs ordrug-polymer matrix formulations. Examples of controlled release systemsare given in U.S. Pat. Nos. 3,845,770; 4,326,525; 4,902,514; and5,616,345. Another formulation for use in the methods of the presentinvention employs transdermal delivery devices (“patches”). Suchtransdermal patches may be used to provide continuous or discontinuousinfusion of the compounds of the present invention in controlledamounts. The construction and use of transdermal patches for thedelivery of pharmaceutical agents is well known in the art. See, e.g.,U.S. Pat. Nos. 5,023,252, 4,992,445 and 5,001,139. Such patches may beconstructed for continuous, pulsatile, or on demand delivery ofpharmaceutical agents.

The compositions may, in some embodiments, be formulated in a unitdosage form. The term “unit dosage forms” refers to physically discreteunits suitable as unitary dosages for human subjects and other mammals,each unit containing a predetermined quantity of active materialcalculated to produce the desired therapeutic effect, in associationwith a suitable pharmaceutical excipient (e.g., a tablet, capsule,ampoule). The compounds are generally administered in a pharmaceuticallyeffective amount. In some embodiments, for oral administration, eachdosage unit contains from about 10 mg to about 1000 mg of a compounddescribed herein, for example from about 50 mg to about 500 mg, forexample about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200mg, about 250 mg, or about 300 mg. In other embodiments, for parenteraladministration, each dosage unit contains from 0.1 to 700 mg of acompound a compound described herein. It will be understood, however,that the amount of the compound actually administered usually will bedetermined by a physician, in the light of the relevant circumstances,including the condition to be treated, the chosen route ofadministration, the actual compound administered and its relativeactivity, the age, weight, and response of the individual subject, andthe severity of the subject's symptoms.

In certain embodiments, dosage levels may be from 0.1 mg to 100 mg perkilogram of body weight per day, for example from about 1 mg to about 50mg per kilogram, for example from about 5 mg to about 30 mg perkilogram. Such dosage levels may, in certain instances, be useful in thetreatment of the above-indicated conditions. In other embodiments,dosage levels may be from about 10 mg to about 2000 mg per subject perday. The amount of active ingredient that may be combined with thevehicle to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. Dosage unitforms may contain from 1 mg to 500 mg of an active ingredient.

Frequency of dosage may also vary depending on the compound used and theparticular disease or condition treated. In some embodiments, forexample, for the treatment of an autoimmune and/or inflammatory disease,a dosage regimen of 4 times daily or less is used. In some embodiments,a dosage regimen of 1 or 2 times daily is used. It will be understood,however, that the specific dose level for any particular subject willdepend upon a variety of factors including the activity of the specificcompound employed, the age, body weight, general health, sex, diet, timeof administration, route of administration, and rate of excretion, drugcombination and the severity of the particular disease in the subjectundergoing therapy.

For preparing solid compositions such as tablets, the principal activeingredient may be mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound of Formula (I), or a pharmaceutically acceptable salt, ester,prodrug, or solvate thereof. When referring to these preformulationcompositions as homogeneous, the active ingredient may be dispersedevenly throughout the composition so that the composition may be readilysubdivided into equally effective unit dosage forms such as tablets,pills and capsules.

The tablets or pills of the compounds described herein may be coated orotherwise compounded to provide a dosage form affording the advantage ofprolonged action, or to protect from the acid conditions of the stomach.For example, the tablet or pill can comprise an inner dosage and anouter dosage component, the latter being in the form of an envelope overthe former. The two components can be separated by an enteric layer thatserves to resist disintegration in the stomach and permit the innercomponent to pass intact into the duodenum or to be delayed in release.A variety of materials can be used for such enteric layers or coatings,such materials including a number of polymeric acids and mixtures ofpolymeric acids with such materials as shellac, cetyl alcohol, andcellulose acetate.

Kits that include a compound of Formula (I), or a pharmaceuticallyacceptable salt, thereof, and suitable packaging are provided. In oneembodiment, a kit further includes instructions for use. In one aspect,a kit includes a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, and instructions for use of the compounds inthe treatment of the diseases or conditions described herein.

Articles of manufacture that include a compound of Formula (I), or apharmaceutically acceptable salt thereof, in a suitable container areprovided. The container may be a vial, jar, ampoule, preloaded syringe,and intravenous bag.

Compounds of Formula (I) may be combined with one or more additionalanti-cancer or anti-inflammatory agents, including any of the following.Various kinase inhibitors are being used and are being developed totreat various cancers. For example, the activation of thephosphatidylinositol 3-kinase (PI3K) pathway is observed in humancancer, and agents inhibiting PI3K are being investigated or developedas potential anti-cancer drugs and for the use in anti-cancer therapies.Additional kinase inhibitors include inhibitors of spleen tyrosinekinase (Syk) and Janus kinase (JAK). Other agents inhibiting relatedpathways are also of interest as anti-cancer or anti-inflammatoryagents, including agents inhibiting the Ras/Raf/MEK/ERK pathway and thePI3K/PTEN/Akt/mTOR pathway. As described herein, such inhibitors includeagents that inhibit all subclasses of a target (e.g. PI3K alpha, beta,delta and gamma), agents that inhibit primarily one subclass, and agentsthat inhibit a subset of all subclasses. Compounds of Formula (I) mayalso be combined with one or more additional anti-cancer oranti-inflammatory agents including inhibitors or antagonists of lysyloxidase-like 2 (LOXL2), and inhibitors or antagonists of adenosine A2Breceptor.

In various aspects, compounds of Formula (I) may be combined with one ormore kinase inhibitors. Examples of kinase inhibitors include PI3Kinhibitors, Syk inhibitors and JAK inhibitors.

Examples of PI3K inhibitors include Compound A, Compound B, and CompoundC:

Additional examples of PI3K inhibitors include XL147, BKM120, GDC-0941,BAY80-6946, PX-866, CH5132799, XL756, BEZ235, and GDC-0980.

Inhibitors of mTOR include OSI-027, AZD2014, and CC-223.

Inhibitors of AKT include MK-2206, GDC-0068 and GSK795.

Examples of Syk inhibitors include compound D:

Additional Syk inhibitors include R788 (fostamatinib), R-406(tamatinib), and PRT062607.

Examples of JAK inhibitors include Compound E:

Additional JAK inhibitors include Ruxolitinib, Tofacitinib, Baricitinib,CYT387, Lestaurtinib, Pacritinib, and TG101348.

In other aspects, compounds of Formula (I) may be combined with one ormore inhibitors or modulators (e.g. antagonists) of LOXL2, adenosine A2Breceptor, MMP-9, ASK1, BTK, mTOR, HDAC, and MEK.

In other aspects, compounds of Formula (I) may be combined with one ormore components of CHOP therapy (cyclophosphamide, Adriamycin,Vincristine, Prednisolone).

In other aspects, compounds of Formula (I) may be combined with one ormore of ribavirin and interferon.

In other aspects, compounds of Formula (I) may be combined with one ormore agents that activate or reactivate latent human immunodeficiencyvirus (HIV). For example, compounds of Formula (I) may be combined witha histone deacetylase (HDAC) inhibitor (listed above) or a proteinkinase C (PKC) activator. For example, compounds of Formula (I) may becombined with romidepsin or panobinostat.

EXAMPLES General Methods

Synthesis of certain compounds, and intermediates used to preparecompounds, is detailed in the following sections. Compound numbers arelisted for convenience.

All operations involving moisture and/or oxygen sensitive materials wereconducted under an atmosphere of dry nitrogen in pre-dried glassware.Unless noted otherwise, materials were obtained from commerciallyavailable sources and used without further purification.

Flash chromatography was performed on an Isco Combiflash Companion usingRediSep Rf silica gel cartridges by Teledyne Isco. Thin layerchromatography was performed using precoated plates purchased from E.Merck (silica gel 60 PF254, 0.25 mm) and spots were visualized withlong-wave ultraviolet light followed by an appropriate staining reagent.

Nuclear magnetic resonance (“NMR”) spectra were recorded on a Varian 400MHz resonance spectrometer. 1H NMR chemical shifts are given in partsper million (δ) downfield from tetramethylsilane (“TMS”) using TMS orthe residual solvent signal (CHCl3=δ 7.24, DMSO=δ 2.50) as internalstandard. 1H NMR information is tabulated in the following format:multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m,multiplet), coupling constant(s) (J) in Hertz, number of protons. Theprefix app is occasionally applied in cases where the true signalmultiplicity was unresolved and br indicates the signal in question wasbroadened.

The compounds were named using ChemBioDraw Ultra Version 12.0.

LCMS analysis was performed using a PE SCIEX API 2000 spectrometer witha Phenomenex Luna 5 micron C18 column.

Preparatory HPLC was performed on a Gilson HPLC 215 liquid handler witha Phenomenex column (Gemini 10□, C18, 110A) and a UV/VIS 156 detector.

When production of starting materials is not particularly described, thecompounds are known or may be prepared analogously to methods known inthe art or as disclosed in the Examples. One of skill in the art willappreciate that synthetic methodologies described herein are onlyrepresentative of methods for preparation of the compounds describedherein, and that other known methods and variants of methods describedherein may be used. The methods or features described in variousExamples may be combined or adapted in various ways to provideadditional ways of making the compounds described herein.

Methods for obtaining the novel compounds described herein will beapparent to those of ordinary skill in the art, procedures described in,for example, the reaction schemes and examples below, and in thereferences cited herein.

EXAMPLES

Methods for obtaining the novel compounds described herein will beapparent to those of ordinary skill in the art, with suitable proceduresbeing described, for example, in the reaction schemes and examplesbelow, and in the references cited herein.

The compound of Formula (1-a) can be prepared by Suzuki coupling of acompound of commercially available compound of Formula (a) tocommercially available isoxazole boronic acid ester shown above in thepresence of a base. Substituents X in compound (a) may be anyappropriate leaving group (e.g., Cl, Br, I, OTf). Suitable catalysts mayinclude palladium catalysts, such as(1,3-bis(2,6-diisopropylphenyl)imidazolidene)(3-chloropyridyl)palladium(II) dichloride (Peppsi-iPr). Suitable bases may include, forexample, cesium carbonate or 1,8-diazobicycloundec-7-ene. Suitablesolvents may include a combination of organic solvents and water,including, for example, 1,4-dioxane, THF, dimethoxyethane ordimethylformamide and water. The reaction is carried out in anappropriate solvent under nitrogen, at an elevated temperature of about70° C. to 150° C., for about 30 seconds to 5 hours. When the reaction issubstantially complete, the reaction is allowed to cool to roomtemperature. The reaction mixture can be partitioned between an aqueousphase and an organic phase. The aqueous phase is discarded, and theorganic phase concentrated under reduced pressure, and the residue ispurified by reverse phase high-performance liquid chromatography,eluting with an appropriate solvent mixture such as acetonitrile andwater, to isolate compounds of Formula (A).

Another exemplary method of preparing compounds of Formula (B) is shownin Reaction Scheme No. 2.

Step 1—Preparation of Formula (B-1)

The compound of Formula (B-1) can be prepared by Suzuki coupling of acompound of commercially available compound chloro-bromo substitutedaromatic heterocycle which may bear an additional heteroaryl ring asshown above as two variable attachment bonds to commercially availableisoxazole boronic acid ester shown above in the presence of a base.Suitable catalysts may include palladium catalysts, such as[1,1′-Bis(diphenylphosphino) ferrocene]dichloropalladium(II). Suitablebases may include, for example, cesium carbonate or1,8-diazobicycloundec-7-ene. Suitable solvents may include a combinationof organic solvents and water, including, for example, 1,4-dioxane, THF,dimethoxyethane or dimethylformamide and water. The reaction is carriedout in an appropriate solvent under nitrogen, at an elevated temperatureof about 70° C. to 150° C., for about 30 seconds to 5 hours. When thereaction is substantially complete, the reaction is allowed to cool toroom temperature. The reaction mixture can be partitioned between anaqueous phase and an organic phase. The aqueous phase is discarded, andthe organic phase concentrated under reduced pressure, and the residueis purified by reverse phase high-performance liquid chromatography,eluting with an appropriate solvent mixture such as acetonitrile andwater, to isolate compounds of Formula (B-1). The compound of Formula(B-1) may also be purified by other conventional means, such as silicagel chromatography.

Step 2—Preparation of Formula (B-2)

The compound of Formula (B-2) can be prepared by Suzuki coupling of acompound of Formula (B-1) to commercially available boronic acidderivatives bearing substituent R³ as defined in the specification forcompounds of Formula (I). Suitable catalysts may include palladiumcatalysts, such as(1,3-bis(2,6-diisopropylphenyl)imidazolidene)(3-chloropyridyl)palladium(II) dichloride (Peppsi-iPr). Suitable bases may include, forexample, cesium carbonate or 1,8-diazobicycloundec-7-ene. Suitablesolvents may include a combination of organic solvents and water,including, for example, 1,4-dioxane, THF, dimethoxyethane ordimethylformamide and water. The reaction is carried out in anappropriate solvent under nitrogen, at an elevated temperature of about70° C. to 150° C., for about 30 seconds to 5 hours. When the reaction issubstantially complete, the reaction is allowed to cool to roomtemperature. The reaction mixture can be partitioned between an aqueousphase and an organic phase. The aqueous phase is discarded, and theorganic phase concentrated under reduced pressure, and the residue ispurified by reverse phase high-performance liquid chromatography,eluting with an appropriate solvent mixture such as acetonitrile andwater, to isolate compounds of Formula (B-2).

Another exemplary method of preparing compounds of Formula (C-2) isshown in Reaction Scheme No. 3.

Step 1—Preparation of Formula (C-1)

An appropriate carbony-delivering reagent is reacted with the compoundof Formula (C-1) (with substituent Q as either H or methyl) in anappropriate solvent, and allowed to react for a period of time such as1-5 hours at an elevated temperature of 80-150° C. Appropriate solventsinclude organic solvents such as tetrahydrofuran. When the reaction issubstantially complete, the compound of (C-1) is isolated by removal ofsolvent under vacuum and purification by conventional means, such asrecrystallization or trituration in an appropriate solvent mixture, suchas hexanes and ethyl acetate.

Step 2—Preparation of Formula (C-2)

The compound of Formula (C-2) can be prepared by Suzuki coupling of acompound of Formula (C-1) to boronic acid shown above in the presence ofa base. As shown above, boronic acid is substituted with carbon-linkedphenyl, naphthyl, or heteroaryl R³ group as defined in the specificationfor compounds of Formula (I). It should be understood that boronateesters, or other appropriate boron complexes (i.e. —BF₃K salts, etc.)may also be used in place of a boronic acid. Suitable catalysts mayinclude palladium catalysts, such as(1,3-bis(2,6-diisopropylphenyl)imidazolidene)(3-chloropyridyl)palladium(II) dichloride (Peppsi-iPr). Suitable bases may include, forexample, cesium carbonate or 1,8-diazobicycloundec-7-ene. Suitablesolvents may include a combination of organic solvents and water,including, for example, 1,4-dioxane, THF, dimethoxyethane ordimethylformamide and water. The reaction is carried out in anappropriate solvent under nitrogen, at an elevated temperature of about70° C. to 150° C., for about 30 seconds to 5 hours. When the reaction issubstantially complete, the reaction is allowed to cool to roomtemperature.

The reaction mixture can be partitioned between an aqueous phase and anorganic phase. The aqueous phase is discarded, and the organic phaseconcentrated under reduced pressure, and the residue is purified byreverse phase high-performance liquid chromatography, eluting with anappropriate solvent mixture such as acetonitrile and water, to isolatecompounds of Formula (C-2). Alternatively, the compound of Formula (C-2)may be purified by other conventional means, such as silica gelchromatography or recrystallization.

When the reactions described herein are substantially complete, thereaction may be allowed to cool to room temperature. The reactionmixture can then be concentrated and purified by any suitable method,including for example, chromatography on silica gel or preparative HPLCto obtain the compound of Formulas (I), (Ia), and (Ib), including eachof the compounds in the examples provided below.

Step 3: Preparation of Formula (C1-C5)

The compound of Formula (C-4, C-5 and C-6) can be prepared as follows:Reacting (C-1) with and appropriate carbonyl source as describedpreviously affords (C-2). (C-2) is then reacted with metalated alkyl oraryl reagents (e.g. but not limited to Li or Mg) to symmetricalcarbinols (C-4), or converted to Weinreb amide (C-3) followed byreaction with metalated alkyl and aryl reagents to afford ketone (C-5).Ketone (C-5) can then we reacted again with metalated alkyl and arylreagents to afford asymmetric carbinol (C-6).

Alternatively, compounds above can be prepared by converting (C-1) tothe corresponding 2-alkoxy-benzimidazole (C-7), which is then furtherconverted to (C-4) including (C-6) using methods above.

The following examples are included to demonstrate certain preferredembodiments. It should be appreciated by those of skill in the art thatthe techniques disclosed in the examples which follow representtechniques discovered by the inventor to function well in the practiceof the invention, and thus can be considered to constitute certainpreferred modes for its practice. However, those of skill in the artshould, in light of the present disclosure, appreciate that many changescan be made in the specific embodiments which are disclosed, and stillobtain a like or similar results without department from the spirit andthe scope of the invention.

The following abbreviations are used in the Examples below:

-   -   DME 1,2-dimethoxy ethane    -   DMF dimethylformamide    -   EtOAc ethyl acetate    -   Hepes 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid    -   mCPBA meta chloroperbenzoic acid    -   MeCN acetonitrile    -   NBS N-bromosuccinimide    -   Peppsi-iPr (or PEPPSI iPr or PEPPSI™-iPr)        (1,3-bis(2,6-diisopropylphenyl)imidazolidene)(3-chloropyridyl)palladium(II)        dichloride    -   PdCl₂dppf [1,1-Bis(diphenylphosphino)        ferrocene]dichloropalladium (II)    -   POCl₃ phosphoryl chloride    -   rf retention factor    -   TEA triethylamine    -   TFA trifluoroacetic acid    -   THF tetrahydrofuran

Example 1N-cyclopentyl-6-(3,5-dimethylisoxazol-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-4-sulfonamide

2,3-Diamino-N-cyclopentyl-5-(3,5-dimethylisoxazol-4-yl)benzenesulfonamide(58 mg, 0.17 mmol) was dissolved in DMF (2 mL). To the solution wasadded CDI (360 mg, 4 mmol) and TEA (1 mL). The reaction was heated at150° C. in microwave for 10 h. The solvent was evaporated and theresidue was purified by preparative HPLC (0-100% CH₃CN/H₂O) to affordN-cyclopentyl-6-(3,5-dimethylisoxazol-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-4-sulfonamide.

C₁₇H₂₀N₄O₄S. 377.0 (M+1). ¹H NMR (400 MHz, CD₃OD) δ 7.34 (s, 1H), 7.18(s, 1H), 3.63-3.58 (m, 1H), 2.41 (s, 3H), 2.25 (s, 3H), 1.70-1.60 (m,4H), 1.49-1.31 (m, 4H).

Example 26-(3,5-dimethylisoxazol-4-yl)-4-(6-methylquinolin-5-yl)-1H-benzo[d]imidazol-2(3H)-one

6-(3,5-Dimethylisoxazol-4-yl)-4-iodo-1H-benzo[d]imidazol-2(3H)-one (38.9mg, 0.11 mmol) was treated with 6-methylquinolin-5-ylboronic acid (30.9mg, 0.165 mmol, 1.5 equiv.), 2M-Na₂CO₃ (aq) (1 mL) in the presence ofPEPPSI iPr (3.7 mg, 0.0055 mmol, 0.05 equiv) in 1,4-dioxane (3 mL) at150° C. for 20 min in microwave reactor (Biotage, Optimizer). To thereaction mixture were added water (30 mL) and EtOAc (70 mL). The wholewas filtered through Celite (3 g) and then organic layer was separatedfrom the filtrate. The organic layer was washed with brine (30 mL) anddried over Na₂SO₄. The solvent was removed under a reduced pressure togive a crude product. The crude product was purified by a preparativeHPLC (5-95% acetonitrile: water with 0.05% trifluoroacetic acid, on aPhenomenex Luna C18 column) and a silica gel chromatography(MeOH:CH₂Cl₂=3:97-10:90) to give6-(3,5-dimethylisoxazol-4-yl)-4-(6-methylquinolin-5-yl)-1H-benzo[d]imidazol-2(3H)-one.

6-(3,5-dimethylisoxazol-4-yl)-4-(6-methylquinolin-5-yl)-1H-benzo[d]imidazol-2(3H)-one:C₂₂H₁₈N₄O₂. MS. m/z 371.1 (M+1). ¹H NMR (MeOH-d₄) δ 9.15 (d, J=5.3 Hz,1H), 8.58 (t, J=8.7 Hz, 1H), 8.58 (d, J=9.0 Hz, 1H), 8.22 (d, J=9.0 Hz,1H), 7.95 (dd, J=8.7, 5.3 Hz, 1H), 7.20 (d, J=1.5 Hz, 1H), 6.95 (d,J=1.5 Hz, 1H), 2.46 (s, 3H), 2.45 (s, 3H), 2.30 (s, 3H).

Example 34,6-bis(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one

4,6-bis(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one wassynthesized using3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazoleand Cs₂CO₃ in a similar fashion as6-(3,5-dimethylisoxazol-4-yl)-4-(6-methylquinolin-5-yl)-1H-benzo[d]imidazol-2(3H)-one(Example 2).

C₁₇H₁₆N₄O₃. MS. 325.1 (M+1). ¹H NMR (MeOH-d₄) δ 7.04 (d, J=1.5 Hz, 1H),6.87 (dd, J=1.5 Hz, 1H), 2.43 (s, 3H), 2.35 (s, 3H), 2.27 (s, 3H), 2.20(s, 3H).

Example 46-(3,5-dimethylisoxazol-4-yl)-4-(2-phenylpyridin-3-yl)-1H-benzo[d]imidazol-2(3H)-one

6-(3,5-dimethylisoxazol-4-yl)-4-(2-phenylpyridin-3-yl)-1H-benzo[d]imidazol-2(3H)-onewas synthsized using 2-phenylpyridin-3-ylboronic acid and Cs₂CO₃ in asimilar fashion as6-(3,5-dimethylisoxazol-4-yl)-4-(6-methylquinolin-5-yl)-1H-benzo[d]imidazol-2(3H)-one(Example 2).

C₂₃H₁₈N₄O₂. MS. 383.1 (M+1). ¹H NMR (MeOH-d₄) δ 8.89 (dd, J=5.7, 1.5 Hz,1H), 8.60 (dd, J=7.9, 1.5 Hz, 1H), 8.04 (dd, J=7.9, 5.7 Hz, 1H),7.51-7.39 (m, 5H), 6.98 (d, J=1.5 Hz, 1H), 6.75 (d, J=1.5 Hz, 1H), 2.19(s, 3H), 2.03 (s, 3H).

Example 54-(3,5-dimethyl-1H-pyrazol-4-yl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one

4-(1,4-dimethyl-1H-pyrazol-5-yl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-onewas synthsized using3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleand Cs₂CO₃ in a similar fashion as6-(3,5-dimethylisoxazol-4-yl)-4-(6-methylquinolin-5-yl)-1H-benzo[d]imidazol-2(3H)-one(Example 2).

C₁₇H₁₇N₅O₂. MS. 324.1 (M+1). ¹H NMR (MeOH-d₄) δ 7.51 (s, 1H), 7.11 (d,J=1.5 Hz, 1H), 6.92 (d, J=1.5 Hz, 1H), 3.74 (s, 3H), 2.43 (s, 3H), 2.28(s, 3H), 2.00 (s, 3H).

Example 65-(6-(3,5-dimethylisoxazol-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-1-methyl-3,4-dihydroquinolin-2(1H)-oneStep 1: Preparation of1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-2(1H)-one

5-bromo-1-methyl-3,4-dihydroquinolin-2(1H)-one (171.4 mg, 0.714 mmol)was treated with4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (272.0 mg,1.071 mmol, 1.5 equiv.), KOAc (210.2 mg, 2.142 mmol, 3.0 equiv) in thepresence of PdCl₂dppf (26.1 mg, 0.0357 mmol, 0.05 equiv) in DMSO (4 mL)at 100° C. for 20 min in a microwave reactor. To the reaction mixturewas added water (30 mL) and EtOAc (70 mL). The mixture was filteredthrough Celite (3 g) and then organic layer was separated from thefiltrate. The organic layer was washed with brine (30 mL) and dried overNa₂SO₄. The solvent was removed under a reduced pressure to give a crudeproduct. The crude product was purified by a preparative HPLC (5-95%acetonitrile: water with 0.05% trifluoroacetic acid, on a PhenomenexLuna C18 column) and a silica gel chromatography(MeOH:CH₂Cl₂=3:97-10:90) to give1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-2(1H)-one(117.2 mg). C₁₆H₂₂BNO₃. MS. m/z 389.1 (M+1).

Step 2: Preparation of5-(6-(3,5-dimethylisoxazol-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-1-methyl-3,4-dihydroquinolin-2(1H)-one

5-(6-(3,5-dimethylisoxazol-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-1-methyl-3,4-dihydroquinolin-2(1H)-onewas synthsized using1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-2(1H)-oneand Cs₂CO₃ in a similar fashion as6-(3,5-dimethylisoxazol-4-yl)-4-(6-methylquinolin-5-yl)-1H-benzo[d]imidazol-2(3H)-one(Example 2).

5-(6-(3,5-dimethylisoxazol-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-1-methyl-3,4-dihydroquinolin-2(1H)-one:C₂₂H₂₀N₄O₃. MS. m/z 389.1 (M+1). ¹H NMR (MeOH-d₄) δ 7.41 (t, J=8.0 Hz,1H), 7.24 (dd, J=8.0, 1.1 Hz, 1H), 7.11 (dd, J=8.0, 1.1 Hz, 1H), 7.02(d, J=1.5 Hz, 1H), 6.84 (d, J=1.5 Hz, 1H), 3.42 (s, 3H), 2.88-2.64 (m,2H), 2.64-2.46 (m, 2H), 2.42 (s, 3H), 2.27 (s, 3H).

Example 75-(3,5-dimethylisoxazol-4-yl)-1-methyl-7-(6-methylquinolin-5-yl)-1H-benzo[d]imidazol-2(3H)-oneStep 1: Preparation of4-(3,5-dimethylisoxazol-4-yl)-2-iodo-N-methyl-6-nitroaniline

Into a flask containing4-(3,5-dimethylisoxazol-4-yl)-2-iodo-6-nitroaniline (1000 mg, 2.78 mmol,1 equiv) is added DMF (15 mL, 0.2 M) before adding cesium carbonate (1.4gm, 4.17 mmol, 1.5 equiv.) and iodomethane (260 μL, 4.17 mmol, 1.5equiv).

After an hour, the reaction was quenched with water and the reaction waspartitioned between water and ethyl acetate. The organic layer waswashed with brine and dried over sodium sulfate. Purification wascarried out by flash column chromatography to furnish4-(3,5-dimethylisoxazol-4-yl)-2-iodo-N-methyl-6-nitroaniline (615 mg,60%).

LCMS (m/z+1) 373.85. ¹H NMR (400 MHz, cdcl₃) δ 7.81 (t, J=3.0 Hz, 1H),7.70 (d, J=2.1 Hz, 1H), 2.97 (s, 3H), 2.40 (d, J=16.8 Hz, 3H), 2.26 (d,J=14.2 Hz, 3H).

Step 2: Preparation of4-(3,5-dimethylisoxazol-4-yl)-6-iodo-N1-methylbenzene-1,2-diamine

Into a microwave vial containing4-(3,5-dimethylisoxazol-4-yl)-2-iodo-N-methyl-6-nitroaniline (610 mg,1.64 mmol, 1 equiv) is added EtOH (12 mL, 0.25M) and tin (II) chloride(622 mg, 3.28 mmol, 2 equiv). The reaction was heated for 30 min at 110°C. The reaction was then stirred in 2N NaOH solution for 20 minutesbefore being partitioned between water and ethyl acetate. The organiclayer was washed with brine and dried over sodium sulfate. Purificationwas carried out by flash column chromatography to furnish4-(3,5-dimethylisoxazol-4-yl)-6-iodo-N1-methylbenzene-1,2-diamine.

LCMS (m/z+1) 344.02.

Step 3: Preparation of5-(3,5-dimethylisoxazol-4-yl)-7-iodo-1-methyl-1H-benzo[d]imidazol-2(3H)-one

Into a flask containing4-(3,5-dimethylisoxazol-4-yl)-6-iodo-N1-methylbenzene-1,2-diamine (299mg, 0.87 mmol, 1 equiv) is added THF (8 mL, 0.1 M) and CDI (282 mg, 1.74mmol, 2 equiv). The reaction was heated for 2 hr at 120° C. The reactionwas then concentrated in vacuo and the solid triturated with diethylether before being air dried to furnish5-(3,5-dimethylisoxazol-4-yl)-7-iodo-1-methyl-1H-benzo[d]imidazol-2(3H)-oneas a light yellow solid.

LCMS (m/z+1) 370.00.

Step 4: Preparation of5-(3,5-dimethylisoxazol-4-yl)-1-methyl-7-(6-methylquinolin-5-yl)-1H-benzo[d]imidazol-2(3H)-one

To a microwave vial containing5-(3,5-dimethylisoxazol-4-yl)-7-iodo-1-methyl-1H-benzo[d]imidazol-2(3H)-one(40 mg, 0.11 mmol, 1 equiv.) was added 3,5-6-methylquinolin-5-ylboronicacid (51 mg, 0.27 mmol, 2.5 equiv.), Cs₂CO₃ (141 mg, 0.43 mmol, 4equiv.) and PEPPSI™-IPr catalyst (8 mg, 0.02 mmol, 0.1 equiv.) anddissolved in DME-H₂O (20 mL, 0.2 M, 2/1, v/v). The mixture was heated to140 C. After 2 hr, the reaction was complete. After cooling, thereaction was extracted with EtOAc and washed with water and saturatedNH₄Cl. After drying with MgSO₄, it was filtered and concentrated todryness. Purification was carried out by reverse phase HPLC to furnish5-(3,5-dimethylisoxazol-4-yl)-1-methyl-7-(6-methylquinolin-5-yl)-1H-benzo[d]imidazol-2(3H)-one.

LCMS (m/z+1) 385.23. ¹H NMR (400 MHz, cd₃od) δ 8.82 (d, J=4.3 Hz, 1H),8.09 (d, J=8.7 Hz, 1H), 7.82 (t, J=7.1 Hz, 2H), 7.47 (dd, J=8.5, 4.3 Hz,1H), 7.17 (d, J=1.6 Hz, 1H), 6.82 (d, J=1.6 Hz, 1H), 2.53 (s, 3H), 2.42(s, 3H), 2.33 (s, 3H), 2.27 (s, 3H).

Example 87-(1,4-dimethyl-1H-pyrazol-5-yl)-5-(3,5-dimethylisoxazol-4-yl)-1-methyl-1H-benzo[d]imidazol-2(3H)-one

To a microwave vial containing5-(3,5-dimethylisoxazol-4-yl)-7-iodo-1-methyl-1H-benzo[d]imidazol-2(3H)-one(40 mg, 0.11 mmol, 1 equiv.) was added1,4-dimethyl-1H-pyrazol-5-ylboronic acid (72 mg, 0.32 mmol, 3 equiv.),Cs₂CO₃ (141 mg, 0.43 mmol, 4 equiv.) and PEPPSI™-IPr catalyst (8 mg,0.02 mmol, 0.1 equiv.) and dissolved in DME-H₂O (20 mL, 0.2 M, 2/1,v/v). The mixture was heated to 140° C. After 1 hr, the reaction wascomplete. After cooling, the reaction was extracted with EtOAc andwashed with water and saturated NH₄Cl. After drying with MgSO₄, it wasfiltered and concentrated to dryness. Purification was carried out byreverse phase HPLC to furnish7-(1,4-dimethyl-1H-pyrazol-5-yl)-5-(3,5-dimethylisoxazol-4-yl)-1-methyl-1H-benzo[d]imidazol-2(3H)-one.

LCMS (m/z+1) 338.19. ¹H NMR (400 MHz, cd₃od) δ 7.44 (s, 1H), 7.15 (d,J=1.6 Hz, 1H), 6.88 (d, J=1.6 Hz, 1H), 3.65 (s, 3H), 0.90 (s, 3H), 2.42(s, 3H), 2.27 (s, 7H), 1.95 (s, 3H).

Example 97-(1,4-dimethyl-1H-pyrazol-5-yl)-5-(3,5-dimethylisoxazol-4-yl)-1-methyl-1H-benzo[d]imidazol-2(3H)-one

To a microwave vial containing5-(3,5-dimethylisoxazol-4-yl)-7-iodo-1-methyl-1H-benzo[d]imidazol-2(3H)-one(40 mg, 0.11 mmol, 1 equiv.) was added 3,5-Dimethylisoxazole-4-boronicacid pinacol ester (72 mg, 0.32 mmol, 3 equiv.), Cs₂CO₃ (141 mg, 0.43mmol, 4 equiv.) and PEPPSI™-IPr catalyst (8 mg, 0.02 mmol, 0.1 equiv.)and dissolved in DME-H₂O (20 mL, 0.2 M, 2/1, v/v). The mixture washeated to 140° C. After 1 hr, the reaction was complete. After cooling,the reaction was extracted with EtOAc and washed with water andsaturated NH₄Cl. After drying with MgSO₄, it was filtered andconcentrated to dryness. Purification was carried out by reverse phaseHPLC to furnish7-(1,4-dimethyl-1H-pyrazol-5-yl)-5-(3,5-dimethylisoxazol-4-yl)-1-methyl-1H-benzo[d]imidazol-2(3H)-one.

LCMS (m/z+1) 339.15. ¹H NMR (400 MHz, cd₃od) δ 7.09 (d, J=1.6 Hz, 1H),6.81 (d, J=1.6 Hz, 1H) 3.11 (d, J=14.5 Hz, 3H), 2.41 (s, 3H), 2.35-2.23(m, 6H), 2.15 (s, 3H).

Example 10 5,7-bis(3,5-dimethylisoxazol-4-yl)benzo[d]oxazol-2(3H)-one

5,7-Dibromobenzo[d]oxazol-2(3H)-one (100.0 mg, 0.341 mmol) was treatedwith3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole(304.7 mg, 1.366 mmol, 4.0 equiv.), 2M-Na₂CO₃ (aq) (1 mL) in thepresence of PEPPSI-IPr (11.6 mg, 0.017 mmol, 0.05 equiv) in 1,4-dioxane(3 mL) at 150° C. for 10 min in microwave reactor To the reactionmixture were added water (30 mL) and EtOAc (70 mL). The mixture wasfiltered through Celite (3 g) and then organic layer was separated fromthe filtrate. The organic layer was washed with brine (30 mL) and driedover Na₂SO₄. The solvent was removed under a reduced pressure to give acrude product. The crude product was purified by a preparative HPLC(5-95% acetonitrile: water with 0.05% trifluoroacetic acid, on aPhenomenex Luna C18 column) and a silica gel column chromatography(MeOH:CH₂Cl₂=3:97-10:90) to give5,7-bis(3,5-dimethylisoxazol-4-yl)benzo[d]oxazol-2(3H)-one.

C₁₇H₁₅N₃O₄. MS. m/z 326.0 (M+1). ¹H NMR (MeOH-d₄) δ 7.08 (s, 1H), 7.01(s, 1H), 2.433 (s, 3H), 2.430 (s, 3H), 2.28 (s, 3H), 2.27 (s, 3H).

Example 115-(3,5-dimethylisoxazol-4-yl)-7-(6-methylquinolin-5-yl)benzo[d]oxazol-2(3H)-oneStep 1

5-Bromo-7-chlorobenzo[d]oxazol-2(3H)-one (100.0 mg, 0.4025 mmol) wastreated with3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole(89.8 mg, 0.4025 mmol, 1.0 equiv.), DBU (183.8 mg, 1.2075 mmol, 3.0equiv.) in the presence of PdCl₂dppf (14.7 mg, 0.02015 mmol, 0.05 equiv)in DMSO (3 mL) and water (1 mL) at 120° C. for 1 h in an oil bath. Tothe reaction mixture were added water (30 mL) and EtOAc (70 mL). Themixture was filtered through Celite (3 g) and then organic layer wasseparated from the filtrate. The organic layer was washed with brine (30mL) and dried over Na₂SO₄. The solvent was removed under a reducedpressure to give a crude product. The crude product was purified by apreparative HPLC (5-95% acetonitrile: water with 0.05% trifluoroaceticacid, on a Phenomenex Luna C18 column) and a silica gel columnchromatography (hexane:EtOAc=1:1) to give7-chloro-5-(3,5-dimethylisoxazol-4-yl)benzo[d]oxazol-2(3H)-one.

C₁₂H₉ClN₂O₃. MS. m/z 265.0 (M−1), 267.0 (M+1).

Step 2

7-Chloro-5-(3,5-dimethylisoxazol-4-yl)benzo[d]oxazol-2(3H)-one (20.8 mg,0.0786 mmol) was treated with 6-methylquinolin-5-ylboronic acid (44.1mg, 0.2358 mmol, 3.0 equiv.), Cs₂CO₃ (153.7 mg, 0.4716 mmol, 6.0 equiv.)in the presence of PEPPSI iPr (2.9 mg, 0.00393 mmol, 0.05 equiv) in1,4-dioxane (3 mL) and water (1 mL) at 150° C. for 1 h in a microwavereactor. To the reaction mixture were added water (30 mL) and EtOAc (70mL). The mixture was filtered through Celite (3 g) and then organiclayer was separated from the filtrate. The organic layer was washed withbrine (30 mL) and dried over Na₂SO₄. The solvent was removed under areduced pressure to give a crude product. The crude product was purifiedby a preparative HPLC (5-95% acetonitrile: water with 0.05%trifluoroacetic acid, on a Phenomenex Luna C18 column) to give5-(3,5-dimethylisoxazol-4-yl)-7-(6-methylquinolin-5-yl)benzo[d]oxazol-2(3H)-one.

C₂₂H₁₇N₃O₃. MS. m/z 372.1 (M+1). ¹H NMR (MeOH-d₄) δ 9.16 (d, J=5.3 Hz,1H), 8.69 (d, J=8.7 Hz, 1H), 8.28 (d, J=8.9 Hz, 1H), 8.21 (d, J=8.9 Hz,1H), 7.97 (dd, J=8.7, 5.3 Hz, 1H), 7.27 (d, J=1.6 Hz, 1H), 7.07 (d,J=1.6 Hz, 1H), 2.49 (s, 3H), 2.45 (s, 3H), 2.30 (s, 3H)

Example 125-(3,5-dimethylisoxazol-4-yl)-7-(2-phenylpyridin-3-yl)benzo[d]oxazol-2(3H)-one

The title compound was synthsized using 2-phenylpyridin-3-ylboronic acidin a similar fashion with5-(3,5-dimethylisoxazol-4-yl)-7-(6-methylquinolin-5-yl)benzo[d]oxazol-2(3H)-one(Example 11).

C₂₃H₁₇N₃O₃. MS. 384.1 (M+1). ¹H NMR (MeOH-d₄) δ 8.02 (dd, J=5.4, 1.5 Hz,1H), 7.68 (dd, J=8.0, 1.5 Hz, 1H), 7.10 (dd, J=8.0, 5.4 Hz, 1H),6.67-6.55 (m, 5H), 6.21 (d, J=1.6 Hz, 1H), 5.97 (d, J=1.6 Hz, 1H), 1.35(s, 3H), 1.19 (s, 3H).

Example 13 and Example 14(R)-6-(3,5-dimethylisoxazol-4-yl)-4-(6-methylquinolin-5-yl)-1H-benzo[d]imidazol-2(3H)-oneand(S)-6-(3,5-dimethylisoxazol-4-yl)-4-(6-methylquinolin-5-yl)-1H-benzo[d]imidazol-2(3H)-one

(R)-6-(3,5-Dimethylisoxazol-4-yl)-4-(6-methylquinolin-5-yl)-1H-benzo[d]imidazol-2(3H)-oneand(S)-6-(3,5-dimethylisoxazol-4-yl)-4-(6-methylquinolin-5-yl)-1H-benzo[d]imidazol-2(3H)-onewere obtained by resolving the racemate (Example 2) by supercriticalfluid chromatography on a chiral column (25% MeOH with 0.1% v/v TFA onan SFC Chiralpak AD-H column.)

First eluting compound:(R)-6-(3,5-dimethylisoxazol-4-yl)-4-(6-methylquinolin-5-yl)-1H-benzo[d]imidazol-2(3H)-one.C₂₂H₁₈N₄O₂. 371.1 (M+1). SFC retention time 3.525 min (Chiralpak AD-H250 mm×10 mm, 16 mL/min, 10 minute run time, 40° C. column oven, 10 MPaback-pressure limiter). ¹H NMR spectra identical to racemic compound.

Second eluting compound:(S)-6-(3,5-dimethylisoxazol-4-yl)-4-(6-methylquinolin-5-yl)-1H-benzo[d]imidazol-2(3H)-one.C₂₂H₁₈N₄O₂. 371.1 (M+1). SFC retention time 4.992 min (Chiralpak AD-H250 mm×10 mm, 16 mL/min, 10 minute run time, 40° C. column oven, 10 MPaback-pressure limiter). ¹H NMR spectra identical to racemic compound.

Example 156-(3,5-dimethylisoxazol-4-yl)-4-(2,4-dimethylpyridin-3-yl)-1H-benzo[d]imidazol-2(3H)-one

6-(3,5-Dimethylisoxazol-4-yl)-4-(2,4-dimethylpyridin-3-yl)-1H-benzo[d]imidazol-2(3H)-onewas synthsized using 2,4-dimethylpyridin-3-ylboronic acid and Cs₂CO₃ ina similar fashion as Example 11.

C₁₉H₁₈N₄O₂. MS. m/z 335.1 (M+1). ¹H NMR (MeOH-d₄) δ 8.65 (d, J=6.2 Hz,1H), 7.93 (d, J=6.2 Hz, 1H), 7.16 (d, J=1.5 Hz, 1H), 6.92 (d, J=1.5 Hz,1H), 2.52 (s, 3H), 2.43 (s, 3H), 2.40 (s, 3H), 2.27 (s, 3H).

Example 164-(6-(3,5-dimethylisoxazol-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)cinnoline-3-carboxylicacid

6-(3,5-dimethylisoxazol-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2(3H)-one(100.0, 0.282 mmol) and 5-bromo-8-chloro-6-methylquinoline (94.0 mg,0.422 mmol) was treated with PdCl2dppf.CH₂Cl₂ (20.6 mg, 0.028 mmol) inthe presence of 1,8-diazabicycloundec-7-ene (DBU, 300.0 mg, 1.971 mmol,7.0 equiv) in DMSO (1 mL) and water (1 mL). The reaction mixture washeated at 110° C. for 12 min in oil bath. The reaction mixture wasinjected into Gilson preparative HPLC to give4-(6-(3,5-dimethylisoxazol-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)cinnoline-3-carboxylicacid.

C₂₁H₁₅N₅O₄. MS. m/z 402.0 (M+1). ¹H NMR (400 MHz, Methanol-d₄) δ 8.67(d, J=8.8 Hz, 1H), 8.09 (t, J=8.8 Hz, 1H), 7.92 (d, J=8.8 Hz, 1H), 7.70(d, J=8.8 Hz, 1H), 7.17 (s, 1H), 6.96 (s, 1H), 2.44 (s, 3H), 2.29 (s,3H).

Example 176-(3,5-dimethylisoxazol-4-yl)-4-(3-methylisoquinolin-4-yl)-1H-benzo[d]imidazol-2(3H)-one

Synthesized in a similar fashion as that of Example 16. C₂₂H₁₈N₄O₂. MS.m/z 371.1 (M+1). ¹H NMR (400 MHz, Methanol-d4) δ 9.26 (s, 1H), 8.16 (d,J=8.6 Hz, 1H), 7.70 (t, J=8.6 Hz, 1H), 7.64 (t, J=8.6 Hz, 1H), 7.42 (d,J=8.6 Hz, 1H), 2.50 (s, 3H), 2.45 (s, 3H), 2.29 (s, 3H).

Example 186-(3,5-dimethylisoxazol-4-yl)-4-(2-methylnaphthalen-1-yl)-1H-benzo[d]imidazol-2(3H)-one

In a 2-5 mL Smith Process Vial,6-(3,5-dimethylisoxazol-4-yl)-4-iodo-1H-benzo[d]imidazol-2(3H)-one(100.0 mg 0.282 mmol), (2-methylnaphthalen-1-yl)boronic acid (176.0 mg,0.946 mmol, 3.36 equiv), PEPPSI-iPr (19.2 mg, 0.028 mmol, 0.1 equiv) andCs₂CO₃ (337.0 mg, 1.126 mmol, 4 equiv) were placed. The mixture wassuspended in 1,4-dioxane (1.5 mL) and water (0.5 mL) under N₂. Themixture was heated at 150° C. for 75 min using microwave reactor(Biotage Optimizer). After an aqueous work up, the crude product waspurified by a silica-gel column chromatography (hexane/EtOAc 20:80) togive6-(3,5-dimethylisoxazol-4-yl)-4-(2-methylnaphthalen-1-yl)-1H-benzo[d]imidazol-2(3H)-one.

C₂₃H₁₉N₃O₂. MS. m/z 370.1 (M+1). ¹H NMR (400 MHz, Methanol-d₄) δ 7.88(d, J=8.6 Hz, 2H), 7.50 (d, J=8.6 Hz, 1H), 7.45-7.38 (m, 1H), 7.38-7.33(m, 2H), 7.10 (s, 1H), 6.82 (s, 1H), 2.43 (s, 3H), 2.28 (s, 6H).

Example 194-(2-(difluoromethyl)-3-methylquinolin-4-yl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one

The title compound was synthesized in a similar fashion as that ofExample 17.

C₂₃H₁₇FN₄O₂. MS. m/z 421.1 (M+1). ¹H NMR (400 MHz, Methanol-d₄) δ 8.18(d, J=9.0 Hz, 1H), 7.83-7.74 (m, 1H), 7.63-7.57 (m, 1H), 7.45 (d, J=9.4Hz, 1H), 7.23-6.87 (m, 2H), 2.47-2.40 (m, 6H), 2.30 (s, 3H).

Example 20 Preparation of4-chloro-5-(3,5-dimethylisoxazol-4-yl)-7-(6-methylquinolin-5-yl)-1H-benzo[d]imidazol-2(3H)-one

In 0.5-2 mL Smith Process Vial, the intermediate (25.0 mg, 0.067 mmol)and NCS (36.3 mg, 0.135 mmol) were dissolved into THF (2 mL). Themixture was heated at 80° C. for 2 h in an oil bath. The reactionmixture was directly injected into Gilson preparative HPLC (5-95%acetonitrile: water with 0.05% trifluoroacetic acid, on a PhenomenexLuna C18 column) to give the desired product.

C19H18N4O2. MS. m/z 405.1 (M+1), 407.1 (M+2+1). ¹H NMR (400 MHz,Methanol-d4) δ 9.25-9.05 (d, J=5.8 Hz, 1H), 8.47-8.40 (m, 1H), 8.30 (d,J=9.0 Hz, 1H), 8.20 (d, J=9.0 Hz, 1H), 7.96-7.90 (m, 1H), 7.19 (s, 1H),2.40 (s, 3/2H), 2.39 (s, 3/2H), 2.38 (s, 3/2H), 2.34 (s, 3/2H) 2.21 (s,3/2H), 2.19 (s, 3/2H).

Example 215-(6-(3,5-dimethylisoxazol-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-6-methyl-1-(2,2,2-trifluoroethyl)quinolin-2(1H)-oneStep 1

5-Bromo-6-methylquinolin-2(1H)-one (103.5 mg, 0.435 mmol) was suspendedinto DMF (3 mL). To the suspension, was added NaH (17.4 mg 60% inmineral oil) at room temperature. After 2 h stirring, CF₃CH₂OTf (201.8mg, 0.869 mmol) was added into the mixture at room temperature. Thereaction mixture was stirred for 2 h at the same temperature. Thereaction mixture was quenched with water (30 mL). The whole wasextracted with AcOEt (30 mL×3). Organic layer was washed with brine (30mL) and dried over Na₂SO₄. The solvent was removed under a reducedpressure to give the crude product. Gilson PHPLC purification gave5-bromo-6-methyl-1-(2,2,2-trifluoroethyl)quinolin-2(1H)-one.

¹H NMR (400 MHz, Methanol-d₄) δ 8.41 (d, J=10.0 Hz, 1H), 7.58 (s, 2H),6.77 (d, J=10.0 Hz, 1H), 5.20 (q, J=8.7 Hz, 2H), 2.52 (d, J=1.0 Hz, 3H).

Step 2

In a 2-5 mL Smith Process Vial, the boronic acid pinacol ester (29.0 mg0.82 mmol), the bromide (26.1 mg, 0.082 mmol, 1 equiv), PEPPSI-iPr (2.8mg, 0.004 mmol, 0.05 equiv) and Cs₂CO₃ (53.2 mg, 0.163 mmol, 2 equiv)were placed. The mixture was suspended in 1,4-dioxane and water underN₂. The mixture was heated at 150° C. for 20 min using microwave reactor(Biotage Optimizer). To the mixture were added EtOAc (70 mL) and water(30 mL). The whole was filtered through Celite (3 g) and the filtratewas washed with brine (30 mL), dried over Na₂SO₄ and concentrated undera reduced pressure. Obtained crude material was purified by Gilsonpreparative HPLC to give the desired product (23.0 mg, 60%).

C₂₄H₁₉F₃N₄O₃. MS. m/z 469.1 (M+1). ¹H NMR (400 MHz, Methanol-d4) δ 7.70(d, J=9.2 Hz, 1H), 7.67 (d, J=9.2 Hz, 1H), 7.52 (d, J=10.0 Hz, 1H), 7.12(s, 1H), 6.82 (s, 1H), 6.60 (d, J=10.0 Hz, 1H), 5.26 (q, J=13.3 Hz, 2H),2.43 (s, 3H), 2.28 (s, 3H), 2.20 (s, 3H).

Example 225-(6-(3,5-dimethylisoxazol-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-1,6-dimethylquinolin-2(1H)-oneStep 1

5-bromo-6-methylquinolin-2(1H)-one (500.0 mg, 2.1 mmol) in THF (10 mL)was treated with KHMDS (2.31 mL, 2.31 mmol, 1.1 equiv) at 0° C. for 15min. To the reaction mixture was added MeI (0.26 mL 596.2 mg, 4.2 mmol,2 equiv) was added into the mixture at 0° C. The reaction mixture wasallowed to warm up to room temperature and stirred for overnight at thesame temperature to form a precipitation. The precipitation was filteredoff using a glass filter. The filtrate was concentrated and purified bya silica-gel column chromatography (hexane/EtOAc 50:50 to 0:100) to give5-(6-(3,5-dimethylisoxazol-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-1,6-dimethylquinolin-2(1H)-oneas colorless crystals.

C₁₁H₁₀BrNO. MS. m/z 469.1 (M+1).

Step 2

5-(6-(3,5-dimethylisoxazol-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-1,6-dimethylquinolin-2(1H)-onewas synthesized in a similar fashion as that of Example 21.

C₂₃H₂₀N₄O₃. MS. m/z 401.1 (M+1). ¹H NMR (400 MHz, Methanol-d₄) δ 7.68(d, J=9.6 Hz, 1H), 7.63 (d, J=9.6 Hz, 1H), 7.45 (d, J=9.6 Hz, 1H), 7.11(s, 1H), 6.80 (s, 1H), 6.58 (d, J=9.6 Hz, 1H), 3.80 (s, 3H), 2.43 (s,3H), 2.28 (s, 3H), 2.20 (s, 3H).

Example 234-(3,5-dicyclopropyl-1H-pyrazol-4-yl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one

The compound of Example 23 was synthesized in a similar fashion as thatof Example 22.

C₂₁H₂₁N₅O₂. MS. m/z 376.1 (M+1). ¹H NMR (400 MHz, Methanol-d₄) δ 7.05(s, 1H), 6.95 (s, 1H), 2.33 (s, 3H), 2.28 (s, 3H), 1.86-1.76 (m, 2H),1.00-0.90 (m, 4H), 0.87-0.78 (m, 4H).

Example 244-(3,5-dicyclopropyl-1-methyl-1H-pyrazol-4-yl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-oneStep 1

4-Bromo-3,5-dicyclopropyl-1-methyl-1H-pyrazole (50.0 mg, 0.22 mmol) wasdissolved into DMF (3 mL). To the solution, was added NaH (17.6 mg 60%in mineral oil, 0.44 mmol, 2 equiv) at room temperature. After 30.minstirring, MeI (62.5 mg, 0.44 mmol, 2 equiv) was added into the mixtureat room temperature. The reaction mixture was stirred for 20 min at thesame temperature. The reaction mixture was quenched with water (30 mL).The whole was extracted with AcOEt (30 mL×3). Organic layer was washedwith brine (30 mL) and dried over Na₂SO₄. The solvent was removed undera reduced pressure to give the crude product. A silica-gel columnchromatography (hexane/EtOAc 87:13 to 70:30) purification gave4-bromo-3,5-dicyclopropyl-1-methyl-1H-pyrazole (51.8 mg, 97.6%).

C₁₀H₁₃BrN₂. MS. m/z 241.0 (M−1+1), 243.0 (M+1+1).

Step 2

4-(3,5-dicyclopropyl-1-methyl-1H-pyrazol-4-yl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-onewas synthesized in a similar fashion as that of Example 21.

C₂₃H₂₀N₄O₃. MS. m/z 390.1 (M+1). ¹H NMR (400 MHz, Methanol-d₄) δ 6.98(s, 1H), 6.85 (s, 1H), 3.87 (s, 3H), 2.43 (s, 3H), 2.27 (s, 3H),1.88-1.80 (m, 1H), 1.69-1.60 (m, 1H), 1.00-0.60 (m, 6H), 0.38-0.28 (m,2H).

Example 256-(3,5-dimethylisoxazol-4-yl)-4-(2-(4-fluorophenyl)pyridin-3-yl)-1H-benzo[d]imidazol-2(3H)-oneStep 1

In a 2-5 mL Smith Process Vial, 2,3-dibromopyridine (300.0 mg, 1.266mmol), 4-fluorophenyl boronic acid (177.2 mg, 1.266 mmol, 1 equiv) andPd(PPh₃)₄ (73.2 mg, 0.063 mmol, 0.05 equiv) were placed. The mixture wassuspended in 1,4-dioxane (3 mL) and 2M-Na₂CO₃ (1 mL) under a nitrogenatmosphere. The mixture was heated at 80° C. for 10 min using themicrowave reactor. To the mixture were added EtOAc (70 mL) and water (30mL). The whole was filtered through Celite (3 g) and the filtrate waswashed with brine (30 mL), dried over Na₂SO₄ and concentrated under areduced pressure. Obtained crude material was purified by Gilsonpreparative HPLC to give 3-bromo-2-(4-fluorophenyl)pyridine.

C₁₁H7BrFN. MS. m/z 241.0 (M−1+1), 243.0 (M+1+1).

Step 2

This transformation was performed in a similar fashion as that ofExample 21.

C₂₃H₁₇FN₄O₂. MS. m/z 401.1 (M+1). ¹H NMR (400 MHz, Methanol-d₄) δ 8.68(dd, 1H, J=4.8, 1.6 Hz), 7.77 (dd, 1H, J=8.0, 1.6 Hz), 7.55 (dd, 1H,J=8.0, 4.6 Hz), 7.42-7.35 (m, 2H), 7.00 (t, 2H, J=8.0 Hz), 6.92 (d, 1H,J=1.0 Hz), 6.65 (d, 1H, J=1.0 Hz), 2.20 (s, 3H), 2.05 (s, 3H).

Example 266-(3,5-dimethylisoxazol-4-yl)-4-(2-(3-fluorophenyl)pyridin-3-yl)-1H-benzo[d]imidazol-2(3H)-one

Step 1

3-Bromo-2-(3-fluorophenyl)pyridine was synthesized in a similar fashionwith 3-bromo-2-(4-fluorophenyl)pyridine. C₁₁H7BrFN. MS. m/z 241.0(M−1+1), 243.0 (M+1+1).

Step 2

This transformation was performed in a similar fashion as that ofExample 21.

C₂₃H₁₇FN₄O₂. MS. m/z 401.1 (M+1). ¹H NMR (400 MHz, Methanol-d₄) δ 8.70(dd, 1H, J=4.8, 1.6 Hz), 7.98 (dd, 1H, J=8.0, 1.6 Hz), 7.57 (dd, 1H,J=8.0, 4.8 Hz), 7.30-7.22 (m, 1H), 7.17-7.10 (m, 2H), 7.06-6.96 (m, 1H),6.93 (d, 1H, J=1.0 Hz), 6.68 (d, 1H, J=1.0 Hz), 2.21 (s, 3H), 2.06 (s,3H).

Example 274-(3,5-dicyclopropylisoxazol-4-yl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-oneStep 1

1,3-Dicyclopropylpropane-1,3-dione (300.0 mg, 1.971 mmol) andhydroxylamine hydrochloride (162.0 mg, 2.365 mmol, 2 equiv) were heatedat 100° C. in DMSO (1 mL) in oil bath. After the reaction completed, thereaction mixture was directly injected into Gilead preparative HPLC togive 4-bromo-3,5-dicyclopropylisoxazole.

C₉H₁₁ON. MS. m/z 228.0 (M−1+1), 230.0 (M+1+1).

Step 2

3,5-Dicyclopropylisoxazole (70.0 mg, 0.469 mmol) was treated with NBS(167.0 mg, 0.938 mmol, equiv) in CH₂Cl₂ at room temperature for 12 h.The solvent was removed under a reduced pressure and the residue wasdirectly loaded onto a silica gel column chromatography (hexane EtOAc87:13) to give 4-bromo-3,5-dicyclopropylisoxazole.

C₉H₁₀BrON. MS. m/z 228.0 (M−1+1), 230.0 (M+1+1).

Step 3

This transformation was performed in a similar fashion as that ofExample 21.

C₂₁H₂₀N₄O₃. MS. m/z 377.1 (M+1). ¹H NMR (400 MHz, Methanol-d₄) δ 7.05(d, 1H, J=1.0 Hz), 6.95 (d, 1H, J=1.0 Hz), 2.43 (s, 3H), 2.28 (s, 3H),1.90 (quin, 1H, J=6.4 Hz), 1.60 (quin, 1H, J=6.4 Hz), 1.01 (d, 4H, J=6.4Hz), 0.91 (d, 4H, J=6.4 Hz).

Example 286-(3,5-dimethylisoxazol-4-yl)-4-(8-fluoro-6-methylquinolin-5-yl)-1H-benzo[d]imidazol-2(3H)-oneStep 1

3,5-Dicyclopropylisoxazole (70.0 mg, 0.469 mmol) was treated with NBS(167.0 mg, 0.938 mmol, 2 equiv) in CH₂Cl₂ at room temperature for 12 h.The solvent was removed under a reduced pressure and the residue wasdirectly loaded onto a silica gel column chromatography (hexane EtOAc87:13) to give 5-bromo-8-fluoro-6-methylquinoline (68.7 mg, 64.2%).

C₉H₁₀BrON. MS. m/z 239.9 (M−1+1), 241.9 (M+1+1).

Step 2

This transformation was performed in a similar fashion as that ofExample 21.

C₂₂H₁₇FN₄O₂. MS. m/z 398.1 (M+1). ¹H NMR (400 MHz, Methanol-d₄) δ 8.93(d, 1H, J=4.0 Hz), 8.08 (d, 1H, J=8.0 Hz), 7.70 (d, 1H, J=11.2 Hz), 7.67(dd, 1H, J=8.0, 4.0 Hz), 7.15 (d, 1H, J=1.0 Hz), 6.88 (d, 1H, J=1.0 Hz),2.43 (s, 3H), 2.38 (s, 3H), 2.28 (s, 3H).

Example 29-(3,5-dicyclopropyl-1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-oneStep 1

4-Bromo-3,5-dicyclopropyl-1-(2,2,2-trifluoroethyl)-1H-pyrazole wassynthesized in a similar fashion with5-bromo-6-methyl-1-(2,2,2-trifluoroethyl)quinolin-2(1H)-one.C₁₁H₁₂BrF₃N₂. MS. m/z 309.0 (M−1+1), 311.0 (M+1+1).

Step 2

This transformation was performed in a similar fashion as that ofExample 21.

C₂₃H₂₂F₃N₅O₂. MS. m/z 458.1 (M+1). ¹H NMR (400 MHz, Methanol-d₄) δ 7.00(d, 1H, J=1.0 Hz), 6.85 (d, 1H, J=1.0 Hz), 4.95 (q, 2H, J=9.6 Hz), 2.43(s, 3H), 2.27 (s, 3H), 1.90-1.81 (m, 1H), 1.66-1.61 (m, 1H), 1.40-1.26(m, 2H), 0.94-0.68 (m, 6H), 0.42-0.32 (m, 2H).

Example 306-(6-(3,5-dimethylisoxazol-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-7-methyl-4,5-dihydro-1H-benzo[b]azepin-2(3H)-oneStep 1

5-Bromo-6-methyl-3,4-dihydroquinolin-2(1H)-one (477.7 mg, 1.998 mmol)was treated with NaN₃ (194.8 mg, 0.938 mmol, 1.5 equiv) in MeSO₃H (3 g)at 0° C. to room temperature for 1 h. The mixture was neutralized withNaHCO₃ and extracted with EtOAc (30 mL×3). The organic layer was washedwith brine (30 mL) and dried over Na₂SO₄. The solvent was removed undera reduced pressure and the crude product was recrystallized from EtOAc(10 mL) to give6-bromo-7-methyl-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one.

C₁₁H₁₂BrON. MS. m/z 254.0 (M−1+1), 256.0 (M+1+1).

Step 2

This transformation was performed in a similar fashion as that ofExample 21.

C₂₃H₂₂N₄O₃. MS. m/z 403.1 (M+1). ¹H NMR (400 MHz, Methanol-d₄) δ 8.93(d, 1H, J=4.0 Hz), 7.24 (d, 1H, J=8.0 Hz), 7.04 (d, 1H, J=8.0 Hz), 7.03(d, 1H, J=1.0 Hz), 6.73 (d, 1H, J=1.0 Hz), 2.60-2.22 (m, 4H), 2.41 (s,3H), 2.26 (s, 3H), 2.05 (s, 3H), 2.04-1.94 (m, 3H).

Example 316-(6-(3,5-dimethylisoxazol-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-7-methyl-4,5-dihydro-1H-benzo[b]azepin-2(3H)-oneStep 1

6-Bromo-7-methyl-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one (100.0 mg,1.998 mmol) was treated with NaH (18.9 mg, 0.472 mmol, 1.2 equiv) in DMF(3 mL) at 0° C. to room temperature for 30 min. To the mixture was addedMeI (111.7 mg, 0.787 mmol, 2 equiv). The mixture was stirred at to roomtemperature for 1 h The mixture was quenched with water and extractedwith EtOAc (30 mL×3). The organic layer was washed with brine (30 mL)and dried over Na₂SO₄. The solvent was removed under a reduced pressureand the crude product was purified by a silica-gel column chromatography(hexane/EtOAc 87:13 to 50:50) to give6-bromo-1,7-dimethyl-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one (88.5 mg,83.9%).

¹H NMR (400 MHz, CDCl₃) δ 7.16 (d, 1H, J=8.0 Hz), 7.03 (d, 1H, J=8.0Hz), 3.32 (s, 3H), 2.43 (s, 3H), 2.40-1.90 (broad, 6H).

Step 2

This transformation was performed in a similar fashion as that ofExample 21.

C₂₄H₂₄N₄O₃. MS. m/z 417.1 (M+1). ¹H NMR (400 MHz, Methanol-d₄) δ 7.34(d, 1H, J=8.0 Hz), 7.30 (d, 1H, J=8.0 Hz), 7.04 (d, 1H, J=1.0 Hz), 6.73(broad, 1H), 3.36 (s, 3H), 2.60-2.20 (m, 4H), 2.41 (s, 3H), 2.26 (s,3H), 2.07 (s, 3H).

Example 324-(8-chloro-6-methylquinolin-5-yl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one

5-Bromo-8-chloro-6-methylquinoline was synthesized in a similar fashion,using 5-bromo-8-fluoro-6-methylquinoline.

C₁₀H₈ClN. MS. m/z 258.0 (M−1+1), 256.1 (M+1+1), 260.0 (M+1+2).

Step 2

A mixture of6-(3,5-Dimethylisoxazol-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2(3H)-one(100.0, 0.282 mmol) and 5-bromo-8-chloro-6-methylquinoline (72.2 mg,0.282 mmol) was treated with PdCl₂dppf-CH₂Cl₂ (20.9 mg, 0.028 mmol) inthe presence of 1,8-Diazabicycloundec-7-ene (DBU, 204.0 mg, 1.34 mmol,4.76 equiv) in DMSO (0.2 mL) and water (0.2 mL). The reaction mixturewas heated at 120° C. in oil bath. The reaction mixture was diluted withTHF (3 mL) and purified by Gilson preparative HPLC to give4-(8-chloro-6-methylquinolin-5-yl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one

C₂₂H₁₇ClN₄O2. ¹H NMR (400 MHz, Methanol-d₄) δ 8.97 (d, 1H, J=4.8, 1.6Hz), 8.08 (d, 1H, J=8.0 Hz), 8.09 (dd, 1H, J=9.6, 1.6 Hz), 8.08 (s, 1H),7.66 (dd, 1H, J=9.6, 4.8 Hz), 7.16 (d, 1H, J=1.0 Hz), 6.89 (d, 1H, J=1.0Hz), 2.44 (s, 3H), 2.36 (s, 3H), 2.28 (s, 3H).

Example 336-(3,5-dimethylisoxazol-4-yl)-4-((7-fluoroquinolin-2-yl)(hydroxy)(phenyl)methyl)-1H-benzo[d]imidazol-2(3H)-oneStep 1

Tert-butyl6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-4-(methoxy(methyl)carbamoyl)-1H-benzo[d]imidazole-1-carboxylatewas dissolved in THF (3 mL). To the solution was added a solution ofphenyl magnesium chloride (2M in THF, 0.508 mmol, 0.254 mmol) at −78° C.after the addition, the reaction was allowed to warm up to roomtemperature. The reaction was stirred for 17 hat the same temperature.The reaction mixture was quenched with water (30 mL). The whole wasextracted with AcOEt (30 mL×3). Organic layer was washed with brine (30mL) and dried over Na₂SO₄. The solvent was removed under a reducedpressure to give the crude product. The crude product was purified by asilica gel column chromatography (hexane: EtOAc, 7:1 to 3:1) to givetert-butyl4-benzoyl-6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazole-1-carboxylate.

C₂₆H₂₇N₃O₅. MS. m/z 462.2 (M+1).

Step 2

To a solution of 7-fluoro-2-bromoquinoline (54.1 mg) in THF (2 mL) wasadded BuLi (1.6 M, 0.25 mL) at −78° C. After 5 min, a solution of phenylketone (60.0 mg) in THF (1 mL) was added at −78° C. The reaction wasimmediately allowed to warm up to room temperature and stirred for 30min. The reaction mixture was quenched with water (30 mL). The whole wasextracted with AcOEt (30 mL×3). Organic layer was washed with brine (30mL) and dried over Na₂SO₄. The solvent was removed under a reducedpressure to give the crude product. The crude product was treated withTFA to cleave the Boc group. The crude product was purified by a silicagel column chromatography (hexane: EtOAc, 7:1 to 3:1) to give tert-butyl4-benzoyl-6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-H-benzo[d]imidazole-1-carboxylate.

C₂₆H₂₇N₃O₅. MS. m/z 509.2 (M+1).

Step 3

Tert-butyl4-benzoyl-6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazole-1-carboxylate(18.0 mg) was dissolved into EtOH (2 mL) and 4M HCl/dioxane (2 mL). Thesolution was heated at 70° C. for 30 min. The reaction mixture wasquenched with water (30 mL). The whole was extracted with EtOAc (30mL×3). Combined organic layers were washed with brine (50 mL). Thesolvent was removed under a reduced pressure to give a crude product.The crude product was purified by a a silica gel column chromatography(hexane: EtOAc, 7:1 to 3:1) to give tert-butyl4-benzoyl-6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazole-1-carboxylate.

C₂₈H₂₁FN₄O₃. MS. m/z 481.1 (M+1). ¹H NMR (400 MHz, Methanol-d₄) δ 8.31(1, J=8.7 Hz, 1H), 8.13 (dd, J=9.2, 5.3 Hz, 1H), 7.67-7.56 (m, 3H),7.40-7.25 (m, 5H), 6.98 (d, J=1.6 Hz, 1H), 6.61 (d, J=1.6 Hz, 1H), 2.28(s, 3H), 2.11 (s, 3H).

Example 346-(3,5-dimethylisoxazol-4-yl)-4-(hydroxy(phenyl)(quinolin-2-yl)methyl)-1H-benzo[d]imidazol-2(3H)-one

(6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazol-4-yl)(phenyl)(quinolin-2-yl)methanolwas synthesized in the similar fashion with tert-butyl4-benzoyl-6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazole-1-carboxylate.

C₃₀H₂₆N₄O₃. MS. m/z 491.2 (M+1).

6-(3,5-dimethylisoxazol-4-yl)-4-(hydroxy(phenyl)(quinolin-2-yl)methyl)-1H-benzo[d]imidazol-2(3H)-onewas synthesized in the similar fashion as that of Example 33.

C₂₈H₂₂N₄O₃. MS. m/z 463.1 (M+1).). ¹H NMR (400 MHz, Methanol-d₄) δ 8.30(d, J=8.6 Hz, 1H), 8.09 (d, J=8.6 Hz, 1H), 7.93 (d, J=8.6 Hz, 1H), 7.77(ddd, J=8.6, 7.0, 1.2 Hz, 1H), 7.61 (ddd, J=8.6, 7.0, 1.2 Hz, 1H), 7.54(d, J=8.6 Hz, 1H), 7.40-7.26 (m, 5H), 6.98 (d, J=1.5 Hz, 1H), 6.61 (d,J=1.5 Hz, 1H), 2.27 (s, 3H), 2.10 (s, 3H).

Example 356-(3,5-dimethylisoxazol-4-yl)-4-(hydroxy(pyridin-2-yl)(quinolin-2-yl)methyl)-1H-benzo[d]imidazol-2(3H)-one

(6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazol-4-yl)(pyridin-2-yl)(quinolin-2-yl)methanolwas synthesized in the similar fashion with tert-butyl4-benzoyl-6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazole-1-carboxylate.

C₂₉H₂₅N₅O₃. MS. m/z 492.2 (M+1).

6-(3,5-dimethylisoxazol-4-yl)-4-(hydroxy(pyridin-2-yl)(quinolin-2-yl)methyl)-1H-benzo[d]imidazol-2(3H)-onewas synthesized in the similar fashion as that of Example 33.

C₂₈H₂₂N₄O₃. MS. m/z 463.1 (M+1).). ¹H NMR (400 MHz, Methanol-d4) δ 8.78(dd, J=6.6, 1.0 Hz, 1H), 8.66 (d, J=8.8 Hz, 1H), 8.47 (td, J=8.8, 1.0Hz, 1H), 8.15-8.03 (m, 3H), 8.00-7.83 (m, 3H), 7.76 (t, J=8.0 Hz, 1H),7.07 (d, J=1.0 Hz, 1H), 6.46 (d, J=1.0 Hz, 1H), 2.22 (s, 3H), 2.04 (s,3H).

Example 366-(3,5-dimethylisoxazol-4-yl)-4-((7-fluoroquinolin-2-yl)(hydroxy)(pyridin-2-yl)methyl)-1H-benzo[d]imidazol-2(3H)-oneStep 1

(6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazol-4-yl)(7-fluoroquinolin-2-yl)(pyridin-2-yl)methanolwas synthesized in the similar fashion with tert-butyl4-benzoyl-6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazole-1-carboxylate.

C₂₉H₂₄FN₅O₃. MS. m/z 510.2 (M+1).

Step 2

6-(3,5-dimethylisoxazol-4-yl)-4-((7-fluoroquinolin-2-yl)(hydroxy)(pyridin-2-yl)methyl)-1H-benzo[d]imidazol-2(3H)-onewas synthesized in the similar fashion as that of Example 33.

C₂₇H₂₀FN₅O₃. MS. m/z 482.1 (M+1). ¹H NMR (400 MHz, Methanol-d₄) δ 8.52(ddd, J=4.9, 1.8, 0.9 Hz, 1H), 8.26 (dd, J=8.9, 0.8 Hz, 1H), 8.04 (dd,J=9.2, 5.3 Hz, 1H), 7.84 (td, J=7.8, 1.8 Hz, 1H), 7.76 (d, J=7.8 Hz,1H), 7.72 (d, J=7.8 Hz, 1H), 7.59 (dd, J=8.9, 1.8 Hz, 1H), 7.54 (d,J=8.9, 0.8 Hz, 1H), 7.33 (ddd, J=7.5, 4.9, 1.2 Hz, 1H), 6.96 (d, J=1.6Hz, 1H), 6.72 (d, J=1.6 Hz, 1H), 2.28 (s, 3H), 2.11 (s, 3H).

Example 37 6-(3,5-dimethylisoxazol-4-yl)-4-((5-fluoropyridin-2-yl)(hydroxy)(pyridin-2-yl)methyl)-1H-benzo[d]imidazol-2(3H)-one

To isopropyl magnesium chloride (1.32 mL, 2.64 mmol, 2 M in THF) intoluene (4 mL) was added 2-bromo-5-fluoropyridine (388 mg, 2.05 mmol) intoluene (1 mL). After 3.5 hours the Grignard solution (1 mL, 0.65 mmol)was added to tert-butyl 6-(3,5-dimethylisoxazol-4-yl)-2ethoxypicolinoyl-1H-benzo[d]imidazole-1-carboxylate (60 mg, 0.13 mmol)in a 1:1 mixture of toluene/2-methyl-THF (6 mL) at 0° C. and the mixturewas allowed to warm to 20° C. After 16 hours, the reaction was quenchedwith saturated NH₄Cl_((aq)) (10 mL), extracted with ethyl acetate (3×10mL), dried over Na₂SO₄, and concentrated in vacuo. The resulting residue(100 mg) was submitted to deprotection directly.

To 100 mg crude tert-butyl6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-4-((5-fluoropyridin-2-yl)(hydroxy)(pyridin-2-yl)methyl)-1H-benzo[d]imidazole-1-carboxylate(100 mg) in ethanol (3 mL) was added hydrochloric acid (0.2 mL, 0.8mmol, 4 M in 1,4-dioxane). The mixture was heated to 70° C. for 0.5hours and then concentrated in vacuo. Purification by reverse-phase HPLC(25-50% acetonitrile/water with 0.01% trifluoroacetic acid, Gemini C185μ) afforded the TFA salt of6-(3,5-dimethylisoxazol-4-yl)-4-((5-fluoropyridin-2-yl)(hydroxy)(pyridin-2-yl)methyl)-1H-benzo[d]imidazol-2(3H)-oneas a light yellow solid.

C₂₃H₁₈FN₅O₃. 432.1 (M+H). ¹H NMR (400 MHz, d3-acetonitrile) δ 10.72 (s,1H), 9.80 (s, 1H), 8.6 (m, 1H), 7.87 (m, 1H), 7.75 (m, 1H), 7.62 (m,1H), 6.87 (s, 1H), 6.51 (s, 1H), 2.30 (s, 3H), 2.11 (s, 3H). ¹⁹F NMR(376 MHz, d₃-acetonitrile) δ −74.7, −130.95.

Example 384-((2,6-difluorophenyl)(5-fluoropyridin-2-yl)(hydroxy)methyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one

To 1-bromo-2,4-difluorobenzene (0.02 ml, 0.16 mmol) in THF (0.52 mL) at−78° C. was added n-butyllithium (0.12 mL, 0.18 mmol, 1.6 M in hexanes).After 30 minutes, tert-butyl6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-4-(5-fluoropicolinoyl)-1H-benzo[d]imidazole-1-carboxylate(50 mg, 0.10 mmol) in THF (1 mL) was added drop-wise to the reaction.After 60 minutes, the reaction was warmed, quenched with saturatedNH₄Cl_((aq)) (10 mL), extracted with ethyl acetate (3×10 mL), dried overNa₂SO₄, and concentrated in vacuo. To the crude residue in ethanol (3.5mL) was added hydrochloric acid (0.35 mL, 1.4 mmol, 4 M in 1,4-dioxane)and the mixture was heated to 70° C. in a microwave reactor for 45minutes. Purification by reverse-phase HPLC (40-50% acetonitrile/waterwith 0.01% trifluoroacetic acid, Gemini C18 5μ) gave thetrifluoroacetate salt of4-((2,6-difluorophenyl)(5-fluoropyridin-2-yl)(hydroxy)methyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-oneas a white solid.

C₂₄H₁₇F₃N₄O₃. 467.03 (M+H). 1H NMR (400 MHz, d₃-acetonitrile) δ 8.74 (s,1H), 8.65 (s, 1H), 8.49 (s, 1H), 7.55 (m, 1H), 6.95 (m, 3H), 6.70 (s,1H), 2.35 (s, 3H), 2.22 (s, 3H). ¹⁹F NMR (377 MHz, d₃-acetonitrile) δ−77, −107, −131.

Example 394-((2,4-difluorophenyl)(5-fluoropyridin-2-yl)(hydroxy)methyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one

In a synthetic process following that described for Example 40, reactionof tert-butyl6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-4-(5-fluoropicolinoyl)-1H-indole-1-carboxylate(50 mg, 0.13 mmol) with the organolithium species resulting frommetal-halogen exchange with 1-bromo-2,4-difluorobenzene in diethyl ethergave, after silica gel chromatography,4-((2,4-difluorophenyl)(5-fluoropyridin-2-yl)(hydroxy)methyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-oneas a white solid.

C₂₄H₁₇F₃N₄O₃. 467.1 (M+H). ¹H NMR (400 MHz, d₃-acetonitrile) δ 8.68 (s,1H), 8.49 (s, 1H), 7.56 (m, 1H), 7.45 (m, 1H), 7.12 (m, 1H), 6.99-6.89(m, 3H), 6.50 (s, 1H), 5.56 (s, 1H), 2.29 (s, 3H), 2.12 (s, 3H). ¹⁹F NMR(377 MHz, d₃-acetonitrile) δ −105, −111, −132.

Example 404-((3,5-difluorophenyl)(5-fluoropyridin-2-yl)(hydroxy)methyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one

In a synthetic process following that described for Example 40, reactionof tert-butyl6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-4-(5-fluoropicolinoyl)-1H-indole-1-carboxylate(50 mg, 0.13 mmol) with the organolithium species resulting from metalhalogen exchange of 1-bromo-3,5-difluorobenzene in diethyl ether gave,after purification of final material by reverse-phase HPLC (40-50%acetonitrile/water with 0.01% trifluoroacetic acid, Gemini C18 5 g) thetrifluoroacetate salt of4-((3,5-difluorophenyl)(5-fluoropyridin-2-yl)(hydroxy)methyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-oneas a white solid.

C24H17F3N4O3. 467.1 (M+H). 1H NMR (400 MHz, d₆-DMSO) δ 10.73 (s, 1H),9.76 (s, 1H), 8.52 (m, 1H), 7.77 (m, 1H), 7.09 (m, 1H), 6.92 (s, 1H),6.33 (s, 1H), 2.25 (s, 3H), 2.07 (s, 3H). ¹⁹F NMR (377 MHz, d₆-DMSO) δ−75, −111, −130.

Example 414-((2,5-difluorophenyl)(5-fluoropyridin-2-yl)(hydroxy)methyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one

In a synthetic process following that described for Example 40, reactionof tert-butyl6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-4-(5-fluoropicolinoyl)-1H-indole-1-carboxylate(50 mg, 0.13 mmol) with the organolithium species resulting from metalhalogen exchange of 1-bromo-2,5-difluorobenzene in diethyl ether gaveafter purification of final material by reverse-phase HPLC (40-50%acetonitrile/water with 0.01% trifluoroacetic acid, Gemini C18 5μ) thetrifluoroacetate salt of4-((2,5-difluorophenyl)(5-fluoropyridin-2-yl)(hydroxy)methyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-oneas a white solid.

C₂₄H₁₇F₃N₄O₃. 466.9 (M+H). ¹H NMR (400 MHz, d₆-DMSO) δ 10.74 (s, 1H),9.87 (s, 1H), 8.48 (m, 1H), 7.75 (m, 1H), 7.64 (m, 1H), 7.30 (s, 1H),7.21-7.07 (m, 3H), 6.86 (s, 1H), 6.38 (s, 1H), 2.26 (s, 3H), 2.07 (s,3H). ¹⁹F NMR (377 MHz, d₆-DMSO) δ −76, −114, −120, −130.

Example 426-(3,5-dimethylisoxazol-4-yl)-4-((5-fluoropyridin-2-yl)(hydroxy)(2,4,5-trifluorophenyl)methyl)-1H-benzo[d]imidazol-2(3H)-one

In a synthetic process following that described for Example 40, reactionof tert-butyl6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-4-(5-fluoropicolinoyl)-1H-indole-1-carboxylate(50 mg, 0.13 mmol) with the organolithium species resulting from metalhalogen exchange of 1-bromo-2,4,5-trifluorobenzene in diethyl ethergave, after purification of final material by reverse-phase HPLC (40-50%acetonitrile/water with 0.01% trifluoroacetic acid, Gemini C18 5μ), thetrifluoroacetate salt of6-(3,5-dimethylisoxazol-4-yl)-4-((5-fluoropyridin-2-yl)(hydroxy)(2,4,5-trifluorophenyl)methyl)-1H-benzo[d]imidazol-2(3H)-oneas a white solid.

C₂₄H₁₆F₄N₄O₃. 485.12 (M+H). ¹H NMR (400 MHz, d₃-acetonitrile), 8.69 (s,1H), 8.49 (s, 1H), 7.59 (m, 1H), 7.13 (m, 1H), 6.98 (s, 1H), 6.52 (m,1H), 2.29 (s, 3H), 2.13 (s, 3H). ¹⁹F NMR (377 MHz, d₃-acetonitrile) δ−77, −110, −137, −135, −145.

Example 436-(3,5-dimethylisoxazol-4-yl)-4-((5-fluoropyridin-2-yl)(hydroxy)(pyrazin-2-yl)methyl)-1H-benzo[d]imidazol-2(3H)-one

In a synthetic process following that described for Example 40, reactionof tert-butyl6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-4-(5-fluoropicolinoyl)-1H-indole-1-carboxylate(50 mg, 0.13 mmol) with the organolithium species resulting fromdeprotonation of pyrazine by LiTMP in THF (using the literature methoddescribed in J. Org. Chem. 1995, 60, 3781-3786.) Following finaldeprotection, the combined organics were washed with water (30 mL) andbrine (30 mL), and dried over Na2SO4. Purification by flashchromatography (0-100% hexanes/ethyl acetate) gave6-(3,5-dimethylisoxazol-4-yl)-4-((5-fluoropyridin-2-yl)(hydroxy)(pyrazin-2-yl)methyl)-1H-benzo[d]imidazol-2(3H)-oneas a white solid.

C22H17FN6O3. 433.1 (M+H). 1H NMR (400 MHz, d3-acetonitrile), 8.88 (s,1H), 8.56-8.44 (m, 3H), 7.72 (m, 1H), 7.61 (m, 1H), 6.97 (s, 1H), 6.57(m, 1H), 2.29 (s, 3H), 2.13 (s, 3H). ¹⁹F NMR (377 MHz, d₃-acetonitrile)δ −130.

Example 446-(3,5-dimethylisoxazol-4-yl)-4-((5-fluoropyridin-2-yl)(hydroxy)(6-(trifluoromethyl)pyridin-2-yl)methyl)-1H-benzo[d]imidazol-2(3H)-oneStep 1

To isopropylmagnesium chloride (0.63 mL, 1.26 mmol, 2 M in THF) intoluene (1.4 mL) was added 2-bromo-5-trifluoromethyl pyridine (300 mg,1.6 mmol) in toluene (4 mL). After 3.5 hours, the Grignard solution (1.9mL, 0.8 mmol) was added to tert-butyl6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-4-formyl-1H-indole-1-carboxylate(100 mg, 0.26 mmol) in toluene (9 mL) at 0° C. and the mixture wasallowed to warm to 20° C. After 16 hours, the reaction was quenched withsaturated NH₄Cl_((aq)) (10 mL), extracted with ethyl acetate (3×10 mL),dried over Na₂SO₄, and concentrated in vacuo. The resulting unpurifiedproduct, 100 mg, was treated to oxidation in 10 mL DCM with Dess-Martinperiodinane reagent (154.1 mg, 0.34 mmol). After 15 minutes, thereaction was quenched with saturated Na₂S₂O_(3(aq)) (10 mL) andextracted with dichloromethane (3×10 mL). The combined organics werewashed with water (30 mL) and brine (30 mL), and dried over Na₂SO₄.Purification by flash chromatography (0-50% ethyl acetate/hexane)afforded tert-butyl6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-4-(6-(trifluoromethyl)picolinoyl)-1H-benzo[d]imidazole-1-carboxylate(30 mg, 23%) as an amber residue contaminated with unreacted aldehyde.

C₂₆H₂₅F₃N₄O₅: 531.0 (M+H).

Step 2

To isopropylmagnesium chloride (1.32 mL, 2.64 mmol, 2 M in THF) intoluene (4 mL) was added 2-bromo-5-fluoropyridine (388 mg, 2.05 mmol) intoluene (1 mL). After 3.5 hours the Grignard solution (1 mL, 0.65 mmol)was added to tert-butyl 6-(3,5-dimethylisoxazol-4-yl)-2ethoxypicolinoyl-1H-benzo[d]imidazole-1-carboxylate (30 mg, 0.13 mmol)in toluene (6 mL) at 0° C. and the mixture was allowed to warm to 20° C.After 16 hours, the reaction was quenched with saturated NH₄C_((aq)) (10mL), extracted with ethyl acetate (3×10 mL), dried over Na₂SO₄, andconcentrated in vacuo. The resulting residue (100 mg) was dissolved inethanol (3 mL) to which was added hydrochloric acid (0.2 mL, 0.8 mmol, 4M in 1,4-dioxane). The mixture was heated to 70° C. for 0.75 hours andthen concentrated in vacuo. Purification by reverse-phase HPLC (25-50%acetonitrile/water with 0.01% trifluoroacetic acid, Gemini C18 5μ)afforded the TFA salt of6-(3,5-dimethylisoxazol-4-yl)-4-((5-fluoropyridin-2-yl)(hydroxy)(6-(trifluoromethyl)pyridin-2-yl)methyl)-1H-benzo[d]imidazol-2(3H)-oneas a light yellow solid.

C₂₄H₁₇F₄N₅O₃. 500.12 (M+H). 1H NMR (400 MHz, d₃-acetonitrile) δ 8.82 (s,1H), 8.76 (s, 1H), 8.45 (d, J=2.7 Hz, 1H), 8.05 (m, 1H), 7.86 (m, 1H),7.75 (m, 2H), 7.62 (m, 1H), 6.93 (s, 1H), 6.58 (s, 1H), 6.93 (s, 1H),6.25 (s, 1H), 2.31 (s, 3H), 2.16 (s, 3H). ¹⁹F NMR (377 MHz,d₃-acetonitrile) δ −68, −76, −131.

Example 45 tert-Butyl6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-4-(hydroxy(5-(trifluoromethyl)pyridin-2-yl)methyl)-1H-benzo[d]imidazole-1-carboxylate

To 2-bromo-5-trifluoromethyl pyridine (200 mg, 0.89 mmol) in THF (4 mL)at −78° C. was added n-butyllithium (0.36 mL, 0.9 mmol, 2.5M inhexanes). After 15 minutes, tert-butyl6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-4-formyl-1H-indole-1-carboxylate(60 mg, 0.16 mmol) in THF (1 mL) was added drop-wise to the reaction.After 60 minutes, the reaction was warmed, quenched with water (10 mL),extracted with ethyl acetate (3×10 mL), dried over Na₂SO₄, andconcentrated in vacuo. Purification of the resulting residue by flashcolumn (0-50% ethyl acetate/hexanes) afforded 30 mg tert-butyl6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-4-(hydroxy(5-(trifluoromethyl)pyridin-2-yl)methyl)-1H-benzo[d]imidazole-1-carboxylatethat was submitted to directly to final deprotection.

30 mg (0.056 mmol) tert-butyl6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-4-(hydroxy(5-(trifluoromethyl)pyridin-2-yl)methyl)-1H-benzo[d]imidazole-1-carboxylatewas dissolved in 3 mL ethanol, and hydrochloric acid (0.1 mL, 0.4 mmol,4 M in 1,4-dioxane) was added. The mixture was heated to 70° C. for 0.5hours and then concentrated in vacuo. Purification by reverse-phase HPLC(25-50% acetonitrile/water with 0.01% trifluoroacetic acid, Gemini C185μ) afforded the TFA salt of6-(3,5-dimethylisoxazol-4-yl)-4-(hydroxy(5-(trifluoromethyl)pyridin-2-yl)methyl)-1H-benzo[d]imidazol-2(3H)-oneas a light yellow solid.

C19H15F31N4O3. 405.1 (M+H). 1H NMR (400 MHz, d3-acetonitrile) δ 8.91 (s,1H), 8.76 (s, 1H), 8.3 (s, 1H), 7.98 (d, J=8.1, 1H), 7.70 (d, J=8.1,1H), 6.71 (m, 2H), 5.98 (s, 1H), 2.24 (s, 3H), 2.08 (s, 3H). ¹⁹F NMR(376 MHz, d₃-acetonitrile) δ −63.45, −74.7.

Example 466-(3,5-dimethylisoxazol-4-yl)-4-(hydroxy(pyrrolidin-2-yl)methyl)-1H-benzo[d]imidazol-2(3H)-one

N-Boc-pyrrolidine (150 mg, 0.39 mmol) and TMEDA (0.2 mL, 158 mg, 1.36mmol) was dissolved in dry MeTHF (2.6 mL) under Ar and cooled to −78° C.Sec-BuLi (1.4M, 0.97 mL, 1.36 mmol) was added dropwise and the reactionwas allowed to stir at −78° C. for 40 mins. tert-butyl6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-4-formyl-1H-benzo[d]imidazole-1-carboxylate(150 mg, 0.39 mmol) was dissolved in MeTHF (0.5 mL) and added dropwisevia syringe to the reaction and allowed to stir at −78° C. for 10minutes. The reaction was quenched with water and extracted three timeswith EtOAc, combined organic layers were washed once with brine,concentrated, and purified by reverse-phase HPLC to give tert-butyl2-((6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazol-4-yl)(hydroxy)methyl)pyrrolidine-1-carboxylate(53 mg, 30%) as a white powder. The solid (50 mg, 0.11 mmol) wasdissolved in EtOH (5 mL) and HCl (1 mL) and heated for 12 hours at 65°C. The reaction was cooled and concentrated to afford the desiredproduct as a white powder.

C₁₇H₂₀N₄O₃ 329.3 (M+1). ¹H NMR (400 MHz, DMSO-d6) δ 10.93 (s, 2H), 10.83(d, J=11.8 Hz, 2H), 9.07 (s, 2H), 8.47 (s, 1H), 7.03 (d, J=1.5 Hz, 1H),6.99 (s, 1H), 6.86 (s, 1H), 6.84 (d, J=1.6 Hz, 1H), 6.38 (d, J=4.0 Hz,1H), 6.10 (d, J=4.2 Hz, 1H), 5.28 (s, 1H), 4.98 (s, 1H), 3.70 (d, J=7.6Hz, 1H), 3.25-3.07 (m, 4H), 2.39 (s, 3H), 2.38 (s, 2H), 2.21 (s, 3H),2.20 (s, 2H), 1.96 (q, J=7.4 Hz, 3H), 1.86 (s, 2H), 1.77 (s, 2H), 1.67(s, 1H). (1:1.4 mixture of diastereomers)

Example 474-(3-cyclopropyl-1-hydroxy-1-(pyridin-2-yl)propyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one

Magnesium metal (39.0 mg, 2.0 mmol) and iodine (one crystal) was takenup in dry diethyl ether (1.2 mL) and (2-bromoethyl)cyclopropane (200 mg,1.3 mmol) was added dropwise until iodine color faded. The remainder wasthen added dropwise over 15 minutes to maintain a gentle reflux and thencooled to 0° C. (2-cyclopropylethyl)magnesium bromide (1.1 M, 0.38 mL,0.41 mmol) was added to a cooled (0° C.) solution of(6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazol-4-yl)(pyridin-2-yl)methanone(50 mg, 0.14 mmol) in dry THF (1.0 mL) under argon and allowed to stirfor 10 minutes. The reaction was quenched with water, extracted threetimes with EtOAc, and combined organic layers were concentrated andpurified by reverse-phase HPLC to give3-cyclopropyl-1-(6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazol-4-yl)-1-(pyridin-2-yl)propan-1-olintermediate. The intermediate was taken up in EtOH (1.5 mL) and 0.2 mLconcentrated HCl and heated to 65° C. for 2 hours and concentrated toafford the desired product as a white powder.

C₂₃H₂₄N₄O₃ 405.2 (M+1). ¹H NMR (400 MHz, Methanol-d4) δ 8.73 (ddd,J=5.8, 1.6, 0.7 Hz, 1H), 8.43 (td, J=8.0, 1.6 Hz, 1H), 8.09 (dt, J=8.2,1.0 Hz, 1H), 7.87 (ddd, J=7.4, 5.7, 1.2 Hz, 1H), 7.13 (d, J=1.5 Hz, 1H),6.96 (d, J=1.4 Hz, 1H), 2.68 (ddd, J=10.6, 8.6, 5.1 Hz, 2H), 2.40 (s,3H), 2.23 (s, 3H), 1.37 (ddd, J=11.8, 7.2, 4.7 Hz, 1H), 1.26-1.13 (m,1H), 0.76-0.66 (m, 1H), 0.43 (ddt, J=8.7, 5.4, 2.4 Hz, 2H), 0.06-−0.05(m, 2H).

Example 486-(3,5-dimethylisoxazol-4-yl)-4-(2-ethyl-1-hydroxy-1-(pyridin-2-yl)butyl)-1H-benzo[d]imidazol-2(3H)-one

(6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazol-4-yl)(pyridin-2-yl)methanone(50 mg, 0.14 mmol) was dissolved in dry THF (1.4 mL) and cooled to 0° C.Pentan-3-ylmagnesium bromide (2.0 M, 0.21 mL, 0.41 mmol) was addeddropwise and the reaction was allowed to stir for 10 mins and thenquenched with water. Reaction was extracted three times with EtOAc andcombined organic layers were washed once with water, concentrated, andpurified by reverse-phase HPLC to give1-(6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazol-4-yl)-2-ethyl-1-(pyridin-2-yl)butan-1-olintermediate. The intermediate was taken up in EtOH (1.5 mL) and 0.2 mLconcentrated HCl and heated to 65° C. for 2 hours and concentrated toafford the desired product as a white powder.

C₂₃H₂₆N₄O₃ 407.3 (M+1). ¹H NMR (400 MHz, Methanol-d4) δ 8.78 (d, J=5.6Hz, 1H), 8.54 (t, J=7.6 Hz, 1H), 8.23 (d, J=7.8 Hz, 1H), 7.98 (t, J=6.4Hz, 1H), 7.21 (d, J=1.2 Hz, 1H), 6.97 (d, J=1.1 Hz, 1H), 2.71 (s, 1H),2.41 (s, 3H), 2.25 (s, 3H), 1.88-1.76 (m, 1H), 1.59-1.29 (m, 3H), 1.09(t, J=7.4 Hz, 3H), 0.85 (t, J=7.5 Hz, 3H).

Example 494-((2,6-difluorophenyl)(hydroxy)(pyrazin-2-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one

n-BuLi (0.58 mL, 0.93 mmol) was added dropwise to a solution of1,3-difluorobenzene (0.102 mL, 0.1 mmol) in THF (5 mL) cooled to −78° C.and allowed to stir for 1 hour. tert-butyl6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-4-formyl-1H-benzo[d]imidazole-1-carboxylate(200 mg, 0.52 mmol) in in THF was added and the reaction was allowed tostir for 5 mins at −78° C., quenched with ammonium chloride, extractedwith EtOAc and concentrated. The crude was then taken up in DCM (2 mL),Des-Martin periodinane (290 mg, 0.78 mmol) was added and the reactionwas allowed to stir for 15 mins. The reaction was quenched with sat.Na2S2O3, extracted with EtOAc, concentrated and purified by silica gelchromatography to give tert-butyl4-(2,6-difluorobenzoyl)-6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazole-1-carboxylate.

n-BuLi (0.21 mL, 0.33 mmol) was added dropwise to a solution of2,2,6,6-tetramethylpiperidine (0.06 mL, 0.33 mmol) in THF (0.7 mL) at 0°C. and was allowed to stir for 5 minutes. Pyrazine (24 mg, 0.3 mmol) inTHF (0.4 mL) was added and the reaction was stirred for an additional 5minutes and then cooled to −78° C. tert-butyl4-(2,6-difluorobenzoyl)-6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazole-1-carboxylate(50 mg, 0.10 mmol) in THF (0.4 mL) was added, the solution was allowedto stir for 5 minutes and then quenched with water. Solution wasextracted three times with EtOAc, washed once with brine andconcentrated. Crude was purified by reverse-phase HPLC and then taken upin EtOH (3 mL) and HCl (0.1 mL) and heated to 65° C. for 2 hours.Reaction was cooled and concentrated to afford desired product as a palebrown powder.

C₂₅H₂₁F₂N₅O₃ 478.5 (M+1). ¹H NMR (400 MHz, Methanol-d4) δ 9.02 (s, 1H),8.57 (d, J=26.1 Hz, 2H), 7.44 (tt, J=8.3, 5.9 Hz, 1H), 7.02-6.89 (m,4H), 2.33 (s, 3H), 2.16 (s, 3H).

Example 504-((2,6-difluorophenyl)(hydroxy)(pyridazin-3-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one

The following compound was made in a similar fashion as that of Example49, but using pyridazine instead of pyrazine.

C₂₅H₂₁F₂N₅O₃ 478.5 (M+1). ¹H NMR (400 MHz, Methanol-d4) δ 9.48 (s, 1H),8.88-8.81 (m, 1H), 8.42 (dd, J=8.7, 5.0 Hz, 1H), 7.54 (tt, J=8.4, 6.1Hz, 1H), 7.05 (dd, J=10.6, 8.6 Hz, 2H), 6.98 (d, J=1.5 Hz, 1H),6.91-6.87 (m, 1H), 2.32 (s, 3H), 2.15 (s, 3H).

Example 51 Example 52, and Example 536-(3,5-dimethylisoxazol-4-yl)-4-((5-fluoropyridin-2-yl)(hydroxy)methyl)-1H-benzo[d]imidazol-2(3H)-one6-(3,5-dimethylisoxazol-4-yl)-4-((5-fluoropyridin-2-yl)(hydroxy)(2,4,6-trifluorophenyl)methyl)-1H-benzo[d]imidazol-2(3H)-oneand6-(3,5-dimethylisoxazol-4-yl)-4-(fluorobis(5-fluoropyridin-2-yl)methyl)-1H-benzo[d]imidazol-2(3H)-one

To isopropylmagnesium chloride (0.63 mL, 1.26 mmol, 2 M intetrahydrofuran) in toluene (1.4 mL) was added 2-bromo-5-fluoropyridine(184.6 mg, 1.05 mmol) in toluene (0.48 mL). After 3.5 hours, theGrignard solution (1.9 mL, 0.65 mmol) was added to tert-butyl6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-4-formyl-1H-indole-1-carboxylate(62.2 mg, 0.16 mmol) in tetrahydrofuran (9 mL) at 0° C. and the mixturewas allowed to warm to 20° C. After 16 hours, the reaction was quenchedwith saturated NH4Cl(aq) (10 mL), extracted with ethyl acetate (3×10mL), dried over Na2SO4, and concentrated in vacuo. Purification by flashchromatography (0-50% ethyl acetate/hexane) afforded tert-butyl6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-4-((5-fluoropyridin-2-yl)(hydroxy)methyl)-1H-benzo[d]imidazole-1-carboxylateas a yellow residue.

To tert-butyl6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-4-((5-fluoropyridin-2-yl)(hydroxy)methyl)-1H-benzo[d]imidazole-1-carboxylate(41.2 mg, 0.09 mmol) in ethanol (5 mL) was added hydrochloric acid (0.66mL, 2.64 mmol, 4 M in 1,4-dioxane). The mixture was heated to 60° C. for6 hours and then concentrated in vacuo. Purification by reverse-phaseHPLC (25-50% acetonitrile/water with 0.01% trifluoroacetic acid, GeminiC18 5μ) afforded6-(3,5-dimethylisoxazol-4-yl)-4-((5-fluoropyridin-2-yl)(hydroxy)methyl)-1H-benzo[d]imidazol-2(3H)-oneas a white solid.

C₁₈H₁₅FN₄O₃. 335.03 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ 10.73 (s, 1H),10.70 (s, 1H), 8.45 (d, J=2.9 Hz, 1H), 7.80 (dd, J=8.7, 4.7 Hz, 1H),7.73 (td, J=8.8, 2.9 Hz, 1H), 6.81 (d, J=1.6 Hz, 1H), 6.74 (d, J=1.5 Hz,1H), 6.03 (s, 1H), 2.31 (s, 3H), 2.12 (s, 3H). 19F NMR (376 MHz,DMSO-d6) δ −76.42, −131.97.

To tert-butyl6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-4-((5-fluoropyridin-2-yl)(hydroxy)methyl)-1H-benzo[d]imidazole-1-carboxylate(57 mg, 0.12 mmol) in dichloromethane (6 mL) was added Dess-Martinperiodinane (154.1 mg, 0.34 mmol). After 15 minutes, the reaction wasquenched with saturated Na2S2O3(aq) (10 mL) and extracted withdichloromethane (3×10 mL). The combined organics were washed with water(30 mL) and brine (30 mL), and dried over Na2SO4. To the crude solutionwas added N,N-diisopropylethylamine (0.05 mL, 0.26 mmol),4-(dimethylamino)pyridine (6.8 mg, 0.05 mmol), and di-tert-butyldicarbonate (120.9 mg). After 90 minutes, the reaction mixture waswashed with water (2×30 mL), dried over Na₂SO₄, and concentrated invacuo. Purification by flash chromatography (0-50% ethyl acetate/hexane)afforded tert-butyl6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-4-(5-fluoropicolinoyl)-1H-benzo[d]imidazole-1-carboxylateas an amber residue.

To 1-bromo-2,4,6-trifluorobenzene (0.02 ml, 0.16 mmol) in diethyl ether(0.52 mL) at −78° C. was added n-butyllithium (0.12 mL, 0.18 mmol, 1.6 Min hexanes). After 30 minutes, tert-butyl6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-4-(5-fluoropicolinoyl)-1H-benzo[d]imidazole-1-carboxylate(50 mg, 0.10 mmol) in diethyl ether (1 mL) was added drop-wise to thereaction. After 60 minutes, the reaction was warmed, quenched withsaturated NH₄Cl_((aq)) (10 mL), extracted with ethyl acetate (3×10 mL),dried over Na₂SO₄, and concentrated in vacuo. To the crude residue inethanol (3.5 mL) was added hydrochloric acid (0.35 mL, 1.4 mmol, 4 M in1,4-dioxane) and the mixture was heated to 70° C. in a microwave reactorfor 45 minutes. Purification by reverse-phase HPLC (40-50%acetonitrile/water with 0.01% trifluoroacetic acid, Gemini C18 5μ)afforded6-(3,5-dimethylisoxazol-4-yl)-4-((5-fluoropyridin-2-yl)(hydroxy)(2,4,6-trifluorophenyl)methyl)-1H-benzo[d]imidazol-2(3H)-oneas a white solid.

C₂₄H₁₆F₄N₄O₃. 485.12 (M+1). ¹H NMR (400 MHz, chloroform-d) δ 9.40 (s,1H), 9.18 (s, 1H), 8.48 (d, J=2.7 Hz, 1H), 7.40 (td, J=8.3, 2.8 Hz, 1H),7.15 (dd, J=8.8, 4.2 Hz, 1H), 6.99 (s, 1H), 6.68-6.56 (m, 3H), 2.31 (s,3H), 2.16 (s, 3H). 19F NMR (377 MHz, chloroform-d) δ −76.51,−102.54-−103.06 (m), −106.62 (p, J=7.9 Hz), −127.18 (dd, J=7.3, 3.8 Hz).

To isopropylmagnesium chloride (0.34 ml, 0.57 mmol, 2 M intetrahydrofuran) in toluene (0.26 mL) was added 2-bromo-5-fluoropyridine(100 mg, 0.57 mmol) in toluene (0.78 mL). After 4 hours, the Grignardsolution (1.2 mL, 0.47 mmol) was added to tert-butyl6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-4-((5-fluoropyridin-2-yl)(hydroxy)methyl)-1H-benzo[d]imidazole-1-carboxylate(57 mg, 0.12 mmol) in tetrahydrofuran (6 mL) at 0° C. After 60 minutes,the reaction was quenched with saturated NH₄Cl_((aq)) (10 mL), extractedwith ethyl acetate (3×10 mL), dried over Na₂SO₄, and concentrated invacuo. To the crude dissolved in ethanol (2.5 mL) was added hydrochloricacid (0.29 mL, 1.17 mmol, 4 M in 1,4-dioxane) and the mixture was heatedto 70° C. in a microwave reactor for 45 minutes. Purification byreverse-phase HPLC (30-45% acetonitrile/water with 0.01% trifluoroaceticacid, Gemini C18 5) afforded4-(bis(5-fluoropyridin-2-yl)(hydroxy)methyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-oneas a white solid.

C₂₃H₁₇F₂N₅O₃. 450.11 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ 10.72 (s, 1H),9.75 (s, 1H), 8.52-8.48 (m, 2H), 7.74 (td, J=8.8, 2.9 Hz, 2H), 7.63 (dd,J=8.9, 4.7 Hz, 2H), 6.84 (d, J=1.2 Hz, 1H), 6.45 (d, J=1.3 Hz, 1H), 2.27(s, 3H), 2.08 (s, 3H). ¹⁹F NMR (376 MHz, DMSO-d₆) δ −75.01, −130.07 (dd,J=8.8, 4.4 Hz).

To4-(bis(5-fluoropyridin-2-yl)(hydroxy)methyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one(10.4 mg, 0.02 mmol) in dichloromethane (2.3 mL) added(diethylamino)sulfur trifluoride (9.15 μl, 0.07 mmol) and stirred for 60minutes before adding more (diethylamino)sulfur trifluoride (0.01 ml,0.07 mmol). After 60 minutes from the second addition, the reaction waspoured into saturated NaHCO_(3(aq)) (5 mL), the layers were separated,and the aqueous was extracted with dichloromethane (2×5 mL). Thecombined organics were dried over Na₂SO₄ and concentrated in vacuo.Purification by reverse-phase HPLC (25-75% acetonitrile/water with 0.01%trifluoroacetic acid, Gemini C18 5) afforded6-(3,5-dimethylisoxazol-4-yl)-4-(fluorobis(5-fluoropyridin-2-yl)methyl)-1H-benzo[d]imidazol-2(3H)-oneas an off-white solid.

C₂₃H₁₆F₃N₅O₂. 452.05 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ 10.85 (s, 1H),10.35 (s, 1H), 8.55 (d, J=2.9 Hz, 2H), 7.82 (td, J=8.6, 2.9 Hz, 2H),7.64 (dd, J=8.8, 4.4 Hz, 2H), 6.92 (s, 1H), 6.40 (s, 1H), 2.27 (s, 3H),2.07 (s, 3H). ¹⁹F NMR (376 MHz, DMSO-d₆) δ −74.14, −127.97 (dt, J=8.3,4.0 Hz), −136.81.

Example 544-((5-chloropyridin-2-yl)(hydroxy)(pyridin-2-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one

To 2-bromo-5-chloropyridine (55.42 mg, 0.29 mmol) in toluene (1 mL) at−78° C. was added n-butyllithium (0.41 mL, 0.65 mmol, 1.6 M intetrahydrofuran). After 60 minutes, tert-butyl6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-4-formyl-1H-indole-1-carboxylate(100 mg, 0.26 mmol) in toluene (0.3 mL) was added drop-wise to thereaction. After 60 minutes, the reaction was warmed, quenched withsaturated NH₄Cl_((aq)) (10 mL), extracted with ethyl acetate (3×10 mL),dried over Na₂SO₄, and concentrated in vacuo. The crude material wasdissolved in dichloromethane (6 mL) and Dess-Martin periodinane (143.06mg, 0.34 mmol) was added. After 10 minutes, the reaction was quenchedwith saturated Na₂S₂O₃(aq) (10 mL) and extracted with dichloromethane(3×10 mL). The combined organics were washed with water (30 mL) andbrine (30 mL), dried over Na₂SO₄, and concentrated in vacuo.Purification by flash chromatography (0-50% ethyl acetate/hexanes)afforded tert-butyl4-(5-chloropicolinoyl)-6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazole-1-carboxylateas an yellow residue.

To 2-bromopyridine (0.02 ml, 0.2 mmol) in tetrahydrofuran (4 mL) at −78°C. was added n-butyllithium (0.15 mL, 0.24 mmol, 1.6 M in hexanes).After 30 minutes, tert-butyl4-(5-chloropicolinoyl)-6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazole-1-carboxylate(33 mg, 0.07 mmol) in tetrahydrofuran (1 mL) was added drop-wise to thereaction. After 30 minutes, the reaction was warmed, quenched withsaturated NH₄C_((aq)) (10 mL), extracted with ethyl acetate (3×10 mL),dried over Na₂SO₄, and concentrated in vacuo. To the crude residue inethanol (3 mL) was added hydrochloric acid (0.17 mL, 0.66 mmol, 4 M in1,4-dioxane) and the mixture was heated to 70° C. in a microwave reactorfor 45 minutes. Purification by reverse-phase HPLC (23-40%acetonitrile/water with 0.01% trifluoroacetic acid, Gemini C18 5 t)afforded4-((5-chloropyridin-2-yl)(hydroxy)(pyridin-2-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-oneas an off-white solid.

C₂₃H₁₈ClN₅O₃. 448.22 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ 10.78 (s, 1H),9.90 (s, 1H), 8.62-8.53 (m, 2H), 8.04-7.96 (m, 2H), 7.66 (dd, J=8.2, 5.2Hz, 2H), 7.53-7.45 (m, 1H), 6.87 (d, J=1.1 Hz, 1H), 6.44 (d, J=1.6 Hz,1H), 2.27 (s, 3H), 2.07 (s, 3H).

Example 554-(bis(5-chloropyridin-2-yl)(hydroxy)methyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one

The following analog was prepared in the same fashion as4-((5-chloropyridin-2-yl)(hydroxy)(pyridin-2-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-oneby substituting 2-bromo-5-chloropyridine for 2-bromopyridine.

4-(bis(5-chloropyridin-2-yl)(hydroxy)methyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-oneas an off-white solid.

C₂₃H₁₇Cl₂N₅O₃. 482.29 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ 10.81 (s, 1H),9.85 (s, 1H), 8.59-8.52 (m, 2H), 8.48 (d, J=3.3 Hz, 1H), 8.01 (dd,J=8.3, 2.5 Hz, 1H), 7.77 (d, J=8.6 Hz, 1H), 7.18 (d, J=5.0 Hz, 1H), 7.06(s, 1H), 6.88 (d, J=1.1 Hz, 1H), 6.34 (d, J=1.5 Hz, 1H), 2.25 (s, 3H),2.05 (s, 3H).

Example 566-(3,5-dimethylisoxazol-4-yl)-4-(hydroxy(pyrazin-2-yl)(2,4,6-trifluorophenyl)methyl)-1H-benzo[d]imidazol-2(3H)-one

To 2,2,6,6-tetramethylpiperidine (0.27 mL, 1.56 mmol) in tetrahydrofuran(16 mL) at −78° C. was added n-butyllithium (0.97 mL, 1.56 mmol, 1.6 Min hexanes). After 5 minutes, the reaction was warmed to 0° C. Afterstirring for 30 minutes, the reaction was cooled to −78° C., andpyrazine (137 mg, 1.69 mmol) in tetrahydrofuran (3.3 mL) and tert-butyl6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-4-formyl-1H-indole-1-carboxylate(498 mg, 1.3 mmol) in tetrahydrofuran (2.6 mL) were added simultaneouslyin a drop-wise manner. After stirring for 60 minutes, the reaction wasquenched with saturated NH₄Cl_((aq)) (10 mL), extracted with ethylacetate (3×10 mL), dried over Na₂SO₄, and concentrated in vacuo.Purification by flash chromatography (0-100% ethyl acetate/hexane)afforded tert-butyl6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-4-(hydroxy(pyrazin-2-yl)methyl)-1H-benzo[d]imidazole-1-carboxylate.To tert-butyl6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-4-(hydroxy(pyrazin-2-yl)methyl)-1H-benzo[d]imidazole-1-carboxylate(50 mg, 0.11 mmol) in dichloromethane (2.5 mL) was added Dess-Martinperiodinane (72.4 mg, 0.16 mmol). After 15 minutes, the reaction wasquenched with saturated Na₂S₂O_(3(aq)) (10 mL) and extracted withdichloromethane (3×10 mL), dried over Na₂SO₄, and concentrated in vacuo.Purification by flash chromatography (0-100% ethyl acetate/hexanes)afforded tert-butyl6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-4-(pyrazine-2-carbonyl)-1H-benzo[d]imidazole-1-carboxylateas a yellow oil.

To 1-bromo-2,4,6-trifluorobenzene (0.01 ml, 0.12 mmol) in diethyl ether(0.5 mL) at −78° C. was added n-_(butyllithium) (0.13 mL, 0.14 mmol, 1.6M in hexanes). After 30 tert-butyl6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-4-(pyrazine-2-carbonyl)-1H-benzo[d]imidazole-1-carboxylate(36.6 mg, 0.08 mmol) in diethyl ether (1 mL) was added drop-wise to thereaction. After 90 minutes, the reaction was warmed, quenched withsaturated NH₄C_((aq)) (10 mL), extracted with ethyl acetate (3×10 mL),dried over Na₂SO₄, and concentrated in vacuo. To the crude residue inethanol (1.5 mL) was added hydrochloric acid (0.20 mL, 0.79 mmol, 4 M in1,4-dioxane) and the mixture was heated to 70° C. in a microwave reactorfor 45 minutes. Purification by reverse-phase HPLC (35-50%acetonitrile/water with 0.01% trifluoroacetic acid, Gemini C18 5)afforded6-(3,5-dimethylisoxazol-4-yl)-4-(hydroxy(pyrazin-2-yl)(2,4,6-trifluorophenyl)methyl)-1H-benzo[d]imidazol-2(3H)-oneas a pale yellow solid.

C₂₃H₁₆F₃N₅O₃. 468.09 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ 10.74 (s, 1H),9.89 (s, 1H), 9.12 (d, J=1.2 Hz, 1H), 8.60-8.49 (m, 2H), 7.39 (s, 1H),7.10 (t, J=9.7 Hz, 2H), 6.83-6.77 (m, 1H), 6.63 (d, J=1.3 Hz, 1H), 2.28(s, 3H), 2.09 (s, 3H). ¹⁹F NMR (377 MHz, DMSO-d₆) δ −74.73, −100.62 (t,J=9.1 Hz), −108.90 (p, J=8.8 Hz).

Example 576-(3,5-dimethylisoxazol-4-yl)-4-(1-methyl-4-phenyl-1H-pyrazol-5-yl)-1H-benzo[d]imidazol-2(3H)-oneStep 1:1-Methyl-4-phenyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

5-bromo-1-methyl-4-phenyl-1H-pyrazole (87 mg, 0.37 mmol) and3,5-Dimethylisoxazole-4-boronic acid pinacol ester (373 mg, 1.47 mmol)was added to a 1,4-dioxane (2 ml). To the above mixture were addedPd(dppf)Cl₂ (27 mg, 0.037 mmol) and potassium acetate (181 mg, 1.85mmol). The reaction mixture was heated at 100° C. for 2 h. The reactionmixture was then diluted with EtOAc (100 ml), washed with bring (50ml×2). The organic solvent was evaporated and the residue was dissolvedin DCM and purified with combi-flash column chromatography (product cameout at 45% EtOAc/Hexane) to afford 141 mg product1-methyl-4-phenyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.

C16H21BN2O2. 285.3 (M+1).

Step 2: Preparation of4-(2-ethoxy-4-(1-methyl-4-phenyl-1H-pyrazol-5-yl)-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole

4-(2-ethoxy-4-iodo-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole (100mg, 0.26 mmol) and1-methyl-4-phenyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(37 mg, 0.13 mmol) was added to a solvent mixture of 1,2-dimethoxyethane(2 ml) and water (1 ml). To the above mixture were added PEPPSI-Ipr (18mg, 0.026 mmol) and CsCO₃ (127 mg, 0.39 mmol). The reaction mixture washeated at 130° C. in microwave reactor for 30 mins. The reaction mixturewas then filtered and organic solvent was evaporated and the residue waspurified with Prep HPLC (0-100% CH₃CN/H₂O) to afford 8 mg product4-(2-ethoxy-4-(1-methyl-4-phenyl-1H-pyrazol-5-yl)-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole.

C₂₄H₂₃N₅O₂. 414.5 (M+1).

Step 3

4-(2-ethoxy-4-(1-methyl-4-phenyl-1H-pyrazol-5-yl)-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole(8 mg, 0.019 mmol) was dissolved in dioxane (0.5 ml), to the solutionwas added concentrated HCl (0.1 ml), heated at 60° C. for 2 h. Solventwas evaporated and the residue was purified with Prep HPLC (0-100%CH3CN/H2O) to afford 2 mg product6-(3,5-dimethylisoxazol-4-yl)-4-(1-methyl-4-phenyl-1H-pyrazol-5-yl)-1H-benzo[d]imidazol-2(3H)-one.

C22H19N5O2. 386.2 (M+1). 1H NMR (400 MHz, CD3OD) δ 8.20 (s, 1H), 7.91(s, 1H), 7.64 (d, J=7.6 Hz, 2H), 7.55 (d, J=7.6 Hz, 2H), 6.94 (s, 1H),6.86 (s, 1H), 3.87 (s, 3H), 2.39 (s, 3H), 2.22 (s, 3H).

Example 586-(3,5-dimethylisoxazol-4-yl)-4-(4-methyl-1-phenyl-1H-pyrazol-5-yl)-1H-benzo[d]imidazol-2(3H)-one

6-(3,5-dimethylisoxazol-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2(3H)-one(30 mg, 0.084 mmol) and 5-bromo-4-methyl-1-phenyl-1H-pyrazole (30 mg,0.13 mmol) was added to a solvent mixture of 1,2-dimethoxyethane (2 ml)and water (1 ml). To the above mixture were added PEPPSI-Ipr (5.4 mg,0.008 mmol) and Cs2CO3 (83 mg, 0.25 mmol). The reaction mixture washeated at 130° C. in microwave reactor for 30 mins. The reaction mixturewas then filtered and organic solvent was evaporated and the residue waspurified with Prep HPLC (0-100% CH3CN/H2O) to afford 3.9 mg product6-(3,5-dimethylisoxazol-4-yl)-4-(4-methyl-1-phenyl-1H-pyrazol-5-yl)-1H-benzo[d]imidazol-2(3H)-one(yield=12%).

C22H19N5O2. 386.3 (M+1). 1H NMR (400 MHz, CD3OD) δ 8.10 (s, 1H), 7.77(d, J=8.0 Hz, 2H), 7.42 (t, J=8.0 Hz, 2H), 7.23-7.22 (m, 2H), 6.94 (s,1H), 2.37 (s, 3H), 2.29 (s, 3H), 2.21 (s, 3H).

The following compounds were made in similar fashion as that of Example58.

Example 596-(3,5-dimethylisoxazol-4-yl)-4-(4-methyl-1-phenyl-1H-pyrazol-3-yl)-1H-benzo[d]imidazol-2(3H)-one

C₂₂H₁₉N₅O₂. 386.1 (M+1). ¹H NMR (400 MHz, CD₃OD) δ 7.98 (s, 1H), 7.73(d, J=8.4 Hz, 2H), 7.58 (d, J=8.4 Hz, 2H), 7.48 (s, 1H), 6.94 (s, 1H),6.90 (s, 1H), 2.34 (s, 3H), 2.19 (s, 3H), 2.10 (s, 3H).

Example 604-(1,4-dicyclopropyl-1H-pyrazol-3-yl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one

C₂₁H₂₁N₅O₂. 376.2 (M+1). ¹H NMR (400 MHz, CD₃OD) δ 7.62 (s, 1H), 7.48(s, 1H), 6.97 (s, 1H), 3.71-3.31 (m, 1H), 2.27 (s, 3H), 2.27 (s, 3H),1.78-1.75 (m, 2H), 1.16-1.06 (m, 2H), 1.05-1.02 (m, 2H), 0.61-0.59 (m,2H).

Example 614-(4-cyclopropyl-1-methyl-1H-pyrazol-5-yl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one

C₁₉H₁₉N₅O₂. 350.2 (M+1). ¹H NMR (400 MHz, CD₃OD) δ 7.19 (s, 1H), 7.00(s, 1H), 6.86 (s, 1H), 3.59 (s, 3H), 2.34 (s, 3H), 2.18 (s, 3H),1.45-1.41 (m, 1H), 0.65-0.63 (m, 2H), 0.45-0.38 (m, 2H).

Example 624-(4-cyclopropyl-1-methyl-1H-pyrazol-3-yl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one

C₁₉H₁₉N₅O₂. 350.2 (M+1). ¹H NMR (400 MHz, CD₃OD) δ 7.53 (s, 1H), 7.30(s, 1H), 6.87 (s, 1H), 3.82 (s, 3H), 2.18 (s, 3H), 1.72 (s, 3H),1.72-1.68 (m, 1H), 0.83-0.75 (m, 2H), 0.50-0.42 (m, 2H).

Example 634-(1,3-dicyclopropyl-1H-pyrrol-2-yl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one

C₂₁H₂₁N₅O₂. 376.2 (M+1). ¹H NMR (400 MHz, CD₃OD) δ 7.23 (s, 1H), 7.09(s, 1H), 6.99 (s, 1H), 3.48-3.42 (m, 3H), 2.27 (s, 3H), 2.00 (s, 3H),1.51-1.23 (m, 1H), 0.91-0.85 (m, 2H), 0.80-0.71 (m, 4H), 0.56-0.46 (m,2H).

Example 644-(2-cyclopropylphenyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one

C₂₁H₁₉N₃O₂. 346.1 (M+1). ¹H NMR (400 MHz, CD₃OD) δ 7.35-7.31 (m, 1H),7.25-7.24 (m, 1H), 7.24-7.03 (m, 1H), 6.99 (s, 1H), 6.87 (s, 1H), 2.42(s, 3H), 2.26 (s, 3H), 1.77-1.73 (m, 1H), 0.79-0.77 (m, 2H), 0.67 (bs,2H).

Example 655-(3,5-dimethylisoxazol-4-yl)-1-methyl-7-(3-methylcinnolin-4-yl)-1H-benzo[d]imidazol-2(3H)-one

C₂₂H₁₉N₅O₂. 386.2 (M+1). ¹H NMR (400 MHz, CD₃OD) δ 8.42 (d, J=8.8 Hz,1H), 7.84 (t, J=7.6 Hz, 1H), 7.73 (t, J=7.6 Hz, 1H), 7.44 (d, J=8.8 Hz,1H), 7.14 (s, 1H), 6.83 (s, 1H), 2.68 (s, 3H), 2.55 (s, 3H), 2.33 (s,3H), 2.17 (s, 3H).

Example 666-(3,5-dimethylisoxazol-4-yl)-4-(4-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-1H-benzo[d]imidazol-2(3H)-one

C₂₁H₂₃N₅O₃. 386.2 (M+1). ¹H NMR (400 MHz, CD₃OD) δ 7.23 (s, 1H), 7.00(s, 1H), 6.86 (s, 1H), 3.83-3.57 (m, 1H), 3.38-3.33 (m, 2H), 2.34 (s,3H), 2.55 (s, 3H), 2.18 (s, 3H), 1.99 (s, 3H), 1.58-1.40 (m, 6H).

Example 674-(2-cyclobutylpyridin-3-yl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one

C₂₁H₂₀N₄O₂. 361.3 (M+1). ¹H NMR (400 MHz, CD₃OD) δ 8.69 (d, J=4.8 Hz,1H), 8.31 (d, J=8.4 Hz, 1H), 7.87-7.83 (m, 1H), 7.04 (s, 1H), 6.85 (s,1H), 3.90-3.86 (m, 1H), 2.33 (s, 3H), 2.30 (bs, 1H), 2.14 (s, 3H), 2.11(bs, 1H), 1.92 (bs, 2H), 1.78-1.71 (m, 2H).

Example 684-(4-amino-2-cyclopropylpyridin-3-yl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one

C₂₀H₁₉N₅O₂. 362.3 (M+1). ¹H NMR (400 MHz, CD₃OD) δ 10.63 (s, 1H), 10.42(s, 1H), 7.82 (s, 1H), 6.81 (s, 1H), 6.61 (s, 1H), 6.40 (s, 1H), 5.21(s, 2H), 2.28 (s, 3H), 2.17 (s, 3H), 1.45-1.43 (m, 1H), 0.98-0.85 (m,2H), 0.69-0.63 (m, 2H), 0.47-0.44 (m, 2H).

Example 694-(4-cyclopropylthiazol-5-yl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one

C₁₈H₁₆N₄O₂S. 353.3 (M+1). ¹H NMR (400 MHz, CD₃OD) δ 8.81 (s, 1H), 6.98(s, 1H), 6.88 (s, 1H), 2.26 (s, 3H), 2.19 (s, 3H), 1.78 (bs, 1H), 0.86(bs, 2H), 0.82 (bs, 2H).

Example 704-([2,3′-bipyridin]-3-yl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one

C₂₂H₁₇N₅O₂. 384.3 (M+1). ¹H NMR (400 MHz, CD₃OD) δ 8.83 (dd, J=1.2, 4.8Hz, 1H), 8.75 (s, 1H), 8.63 (d, J=5.2 Hz, 1H), 8.23 (d, J=7.2 Hz, 1H),8.08 (dd, J=1.2, 8.0 Hz, 1H), 7.72-7.67 (m, 2H), 6.99 (d, J=1.2 Hz, 1H),6.86 (s, 1H), 2.29 (s, 3H), 2.12 (s, 3H).

Example 714-(4-cyclopropylpyridin-3-yl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one

C₂₀H₁₈N₄O₂. 347.3 (M+1). ¹H NMR (400 MHz, CD₃OD) δ 8.34 (d, J=6.4 Hz,1H), 8.28 (s, 1H), 6.98-6.97 (m, 1H), 6.93 (d, J=6.4 Hz, 1H), 6.84 (d,J=1.2 Hz, 1H), 2.34 (s, 3H), 2.17 (s, 3H), 1.85-1.75 (m, 1H), 0.95 (bs,2H), 0.78 (bs, 2H).

Example 724-(3-cyclopropylpyridin-4-yl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one

C₂₀H₁₈N₄O₂. 347.3 (M+1). ¹H NMR (400 MHz, CD₃OD) δ 8.58 (d, J=5.2 Hz,1H), 8.43 (s, 1H), 7.82 (d, J=6.4 Hz, 1H), 7.05 (d, J=1.2 Hz, 1H), 6.94(d, J=1.6 Hz, 1H), 2.34 (s, 3H), 2.18 (s, 3H), 1.88-1.84 (m, 1H),1.00-0.95 (m, 2H), 0.85-0.81 (m, 2H).

Example 734-(2-cyclopropylpyridin-3-yl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one

C₂₀H₁₈N₄O₂. 347.2 (M+1). 1H NMR (400 MHz, CD₃OD) δ 8.57 (d, J=8.4 Hz,1H), 8.19 (d, J=8.4 Hz, 1H), 7.70-7.67 (m, 1H), 7.10 (s, 1H), 6.99 (s,1H), 2.43 (s, 3H), 2.27 (s, 3H), 2.14-2.08 (m, 1H), 1.15 (bs, 4H).

Example 742-cyclopropyl-3-(6-(3,5-dimethylisoxazol-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)pyridine1-oxide

4-(2-cyclopropylpyridin-3-yl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one(35 mg, 0.1 mmol) was dissolved in MeOH/DCM (1/1 mL). To the solutionwas added 3-Chloroperoxybenzoic acid (69.75 mg, 0.4 mol) and the mixturestirred at RT overnight. The organic solvent was evaporated and theresidue was purified with Prep HPLC (0-100% CH₃CN/H₂O) to afford2-cyclopropyl-3-(6-(3,5-dimethylisoxazol-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)pyridine1-oxide.

C₂₀H₁₈N₄O₃. 363.2 (M+1). ¹H NMR (400 MHz, CD₃OD) δ 8.47 (dd, J=1.2, 6.4Hz, 1H), 7.64 (dd, J=1.2, 6.4 Hz, 1H), 7.54 (t, J=6.4 Hz, 1H), 7.08 (d,J=1.2 Hz, 1H), 6.94 (d, J=1.2 Hz, 1H), 2.42 (s, 3H), 2.25 (s, 3H),2.04-1.99 (m, 1H), 0.96 (bs, 1H), 0.75 (bs, 1H), 0.61 (bs, 1H), 0.54(bs, 1H).

Example 754-(5-amino-2-cyclopropylpyridin-3-yl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one

6-(3,5-dimethylisoxazol-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2(3H)-one(150 mg, 0.42 mmol) and 5-bromo-6-cyclopropylpyridin-3-amine (180 mg,0.84 mmol) were added to a solvent mixture of 1,2-dimethoxyethane (2 mL)and water (1 mL). To the mixture were added PEPPSI-Ipr (29 mg, 0.03mmol) and Cs₂CO₃ (413 mg, 1 mmol). The reaction mixture was heated at130° C. in microwave reactor for 30 mins. The reaction mixture was thenfiltered and organic solvent was evaporated and the residue was purifiedwith Prep HPLC (0-100% CH₃CN/H₂O) to afford 129 mg of4-(5-amino-2-cyclopropylpyridin-3-yl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one.

C20H19N5O2. 362.1 (M+1). 1H NMR (400 MHz, CD3OD) δ 10.98 (s, 1H), 10.81(s, 1H), 7.79 (s, 1H), 7.05 (s, 1H), 6.99 (s, 2H), 2.26 (s, 3H), 2.18(s, 3H), 1.62 (bs, 1H), 0.82 (bs, 2H), 0.62 (bs, 2H).

Example 766-cyclopropyl-5-(6-(3,5-dimethylisoxazol-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)nicotinonitrile

4-(5-amino-2-cyclopropylpyridin-3-yl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one(21 mg, 0.058 mmol) was suspended in a mixture of water (1 mL) and con.HCl (1 mL), cooled suspension to 0° C., a solution of sodium nitrite (4mg, 0.058 mmol) in water was added slowly. After 5 mins, the reactionmixture was neutralised by the addition of NaHCO₃ solution. Then theresultant suspension was added in aliquots to a solution of copper (I)cyanide (5 mg, 0.058 mmol) and sodium cyanide (6 mg, 0.11 mmol) in waterat room temperature. Heated to 70° C. for 30 mins. Extracted with EtOAc,evaporated organic solvent, the residue was purified with Prep HPLC.(0-100% CH₃CN/H₂O) to afford 1.2 mg of6-cyclopropyl-5-(6-(3,5-dimethylisoxazol-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)nicotinonitrile.

C21H17N5O2. 372.4 (M+1). 1H NMR (400 MHz, CD3OD) δ 8.63 (s, 1H), 7.79(s, 1H), 7.06 (s, 1H), 6.99 (s, 1H), 2.25 (s, 3H), 2.18 (s, 3H),1.88-1.80 (m, 1H), 0.88-0.83 (m, 2H), 0.78-0.75 (m, 2H).

Example 774-(5-bromo-2-cyclopropylpyridin-3-yl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one

4-(5-amino-2-cyclopropylpyridin-3-yl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one(75 mg, 0.21 mmol) was dissolved in acetonitrile (2 ml), at roomtemperature added tert-butyl nitrite (32 mg, 0.31 mmol) and CuBr₂ (56mg, 0.25 mmol), stirred at room temperature for 1 h. The reactionmixture was diluted with EtOAc, washed with brine, evaporated organicsolvent, purified with Prep HPLC. (0-100% CH₃CN/H₂O) to afford 6 mg of4-(5-bromo-2-cyclopropylpyridin-3-yl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one.

C20H17BrN4O2. 425.3 (M+1). 1H NMR (400 MHz, CD3OD) δ 8.42 (s, 1H), 7.61(s, 1H), 6.99 (s, 1H), 6.96 (s, 1H), 2.33 (s, 3H), 2.18 (s, 3H),1.78-1.70 (m, 1H), 0.88-0.81 (m, 2H), 0.71-0.64 (m, 2H).

Example 78N-(6-cyclopropyl-5-(6-(3,5-dimethylisoxazol-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)pyridin-3-yl)acetamide

4-(5-Amino-2-cyclopropylpyridin-3-yl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one(75 mg, 0.21 mmol) was dissolved in acetonitrile (2 mL), at roomtemperature added tert-butyl nitrite (32 mg, 0.31 mmol) and CuBr₂ (56mg, 0.25 mmol), stirred at room temperature for 1 h. The reactionmixture was diluted with EtOAc, washed with brine, evaporated organicsolvent, purified with Prep HPLC. (0-100% CH₃CN/H₂O) to afford 16 mg ofN-(6-cyclopropyl-5-(6-(3,5-dimethylisoxazol-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)pyridin-3-yl)acetamide.

C₂₂H₂₁N₅O₃. 404.4 (M+1). ¹H NMR (400 MHz, CD₃OD) δ 8.89 (s, 1H), 7.78(s, 1H), 7.06 (s, 1H), 7.03 (s, 1H), 2.33 (s, 3H), 2.17 (s, 3H), 2.12(s, 3H), 1.82-1.78 (m, 1H), 0.99-0.94 (m, 2H), 0.77-0.74 (m, 2H).

Example 794-(4-bromo-2-cyclopropylpyridin-3-yl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one

4-(4-bromo-2-cyclopropylpyridin-3-yl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-onewas made in similar fashion to4-(5-bromo-2-cyclopropylpyridin-3-yl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one

C₂₀H₁₇BrN₄O₂. 425.3 (M+1). 1H NMR (400 MHz, CD₃OD) δ 8.18 (d, J=2.8 Hz,1H), 7.55 (d, J=2.8 Hz, 1H), 6.98 (s, 1H), 6.78 (s, 1H), 2.35 (s, 3H),2.20 (s, 3H), 1.75-1.65 (m, 1H), 1.03-0.88 (m, 2H), 0.82-0.68 (m, 2H).

Example 804-(2,4-dicyclopropylpyridin-3-yl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one

4-(4-bromo-2-cyclopropylpyridin-3-yl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one(17 mg, 0.04 mmol) and cyclopropyl boronic acid (100 mg, 1.2 mmol) weredissolved in dioxane (2 mL). To the reaction mixture were added K₃PO₄(50 mg, 0.24 mol) and dichloro 1,1′-bis(diphenylphosphino)ferrocenepalladium (II) dichloromethane (10 mg, 0.012 mmol). The reaction mixturewas heated at 100° C. for 3 h. Solvent was evaporated, the residue wasdissolved in EtOAc, washed with brine, evaporated organic solvent andthe residue was purified with Prep HPLC (0-100% CH₃CN/H₂O) to afford 5.4mg of4-(2,4-dicyclopropylpyridin-3-yl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one.

C23H22N4O2. 387.3 (M+1). 1H NMR (400 MHz, CD3OD) δ 8.30 (d, J=6.4 Hz,1H), 7.19 (d, J=6.4 Hz, 1H), 7.05 (s, 1H), 6.91 (s, 1H), 2.38 (s, 3H),2.21 (s, 3H), 1.95-1.88 (m, 1H), 1.72-1.67 (m, 1H), 1.17-1.14 (m, 2H),1.07-0.95 (m, 6H).

Example 816-(3,5-dimethylisoxazol-4-yl)-4-(6-(trifluoromethoxy)quinolin-5-yl)-1H-benzo[d]imidazol-2(3H)-oneStep 1

Degassed dioxane (120 mL) was added to a round-bottom flask containing6-(3,5-dimethylisoxazol-4-yl)-4-iodo-1H-benzo[d]imidazol-2(3H)-one (6 g,16.9 mmol), dppfPdCl₂ (630 mg, 5%), KOAc, (3.3 g, 2 equiv) andbispinacolato diboron (8.6 g, 2 equiv). The reaction mixture wassonicated to eliminate lumps, and was then heated to 120° C. overnight.The reaction was complete via TLC and HPLC analysis. The reactionmixture was dry-loaded onto silica gel and purified by flashchromatography (rf 0.4 in ethyl acetate, eluting with ethylacetate/methanol.6-(3,5-dimethylisoxazol-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2(3H)-onewas isolated and subjected to high-vacuum drying overnight, andcontained an equivalent of pinacol side-products by NMR.

Step 2

A solution of 5-bromo-6-(trifluoromethoxy)quinoline (obtained bybromination of 6-trifluoromethoxyquinoline) (50 mg, 0.17 mmol),6-(3,5-dimethylisoxazol-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2(3H)-one(91 mg, 0.26 mmol), dichloro 1,1-bis(diphenylphosphino)ferrocenepalladium(II) dichloromethane (12.7 mg, 0.02 mmol),1,8-diazabicyclo[5.4.0]undec-7-ene (0.2 mL, 1.37 mmol), DMSO (0.2 mL)and water (0.2 mL) under nitrogen was heated at 120° C. for 1 h. Thereaction mixture was filtered and purified by reverse-phase HPLC to give6-(3,5-dimethylisoxazol-4-yl)-4-(6-(trifluoromethoxy)quinolin-5-yl)-1H-benzo[d]imidazol-2(3H)-one.

C₂₂H₁₅F₃N₄O₃. 441.1 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ 10.88 (s, 1H),10.53 (d, J=2.0 Hz, 1H), 9.00 (dd, J=4.2, 1.7 Hz, 1H), 8.25 (d, J=9.3Hz, 1H), 7.94-7.82 (m, 2H), 7.58 (dd, J=8.6, 4.2 Hz, 1H), 7.08-6.97 (m,1H), 6.88 (d, J=1.5 Hz, 1H), 2.39 (s, 3H), 2.21 (s, 3H).

Example 824-(5,7-difluoroquinolin-4-yl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one

A mixture of6-(3,5-dimethylisoxazol-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2(3H)-one(0.05 g), commercially available 4-bromo-5,7-difluoroquinoline (0.137g), Peppsi catalyst (0.009 g), and Cs₂CO₃ (0.183 g) were stirred underN₂ in water/dioxane (1 mL each) at 140° C. for 30 min. After cooling toroom temperature, brine (1 mL) was added, the organic layer separatedand volatiles removed under vacuum. The residue was purified bypreparative HPLC (5-95% MeCN in H₂O) to afford the title compound.

C₂₁H₁₄F₂N₄O₂; 393.20 (M+1). ¹H NMR (400 MHz, DMSO-d6) δ 10.85 (s, ¹H),10.59 (d, J=1.7 Hz, 1H), 9.01 (d, J=4.5 Hz, 1H), 7.78 (dt, J=9.6, 1.7Hz, 1H), 7.66-7.37 (m, 2H), 6.95 (dt, J=18.3, 1.2 Hz, 2H), 2.38 (s, 3H),2.32 (s, 3H).

Example 834-(5,8-difluoroquinolin-4-yl)-6-(3,5-dimethylisoxazol-4-yl)-H-benzo[d]imidazol-2(3H)-one

4-(5,8-difluoroquinolin-4-yl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-onewas made in a similar fashion as that of Example 82.

C21H14F2N4O2; 393.18 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 10.85 (d, J=1.5Hz, 1H), 10.57 (d, J=1.8 Hz, 1H), 9.03 (d, J=4.4 Hz, 1H), 7.76-7.60 (m,1H), 7.35 (ddd, J=12.3, 8.7, 3.9 Hz, 1H), 6.94 (dd, J=13.6, 1.6 Hz, 2H),2.39 (s, 3H), 2.21 (s, 3H).

Example 844-(5-chloroquinolin-4-yl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one

The boronic acid (0.05 g), bromide (0.137 g), Peppsi catalyst (0.009 g),Cs2CO3 (0.183 g) was stirred under N2 in water/dioxane (1 ml each) at140 C for 30 min. After cooling to RT, brine (1 mL) was added, theorganic layer separated and volatiles removed under vacuum. The residuewas purified by preparative HPLC (5-95% MeCN in H2O) to afford the titlecompound.

C21H15ClN4O2; 391.15 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 10.78 (d, J=1.9Hz, 1H), 10.52 (d, J=1.9 Hz, 1H), 8.63 (d, J=5.6 Hz, 1H), 8.11 (dd,J=6.8, 2.6 Hz, 1H), 8.04 (d, J=5.7 Hz, 0H), 7.83-7.72 (m, 1H), 2.36 (s,3H), 2.18 (s, 3H).

The following compounds were prepared in a similar fashion to that ofExample 82, using the appropriate bromo or chloro derivative:

Example 856-(3,5-dimethylisoxazol-4-yl)-4-(6-(2,2,2-trifluoroethoxy)quinolin-5-yl)-1H-benzo[d]imidazol-2(3H)-one

C₂₃H₁₇F₃N₄O₃. 455.1 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ 10.77 (d, J=2.0Hz, 1H), 10.38 (d, J=2.0 Hz, 1H), 8.87 (dd, J=4.5, 1.6 Hz, 1H), 8.17 (d,J=9.3 Hz, 1H), 7.89 (dd, J=9.0, 5.4 Hz, 2H), 7.52 (dd, J=8.6, 4.2 Hz,1H), 6.97 (d, J=1.5 Hz, 1H), 6.81 (d, J=1.6 Hz, 1H), 4.86 (ddq, J=56.9,12.0, 8.9 Hz, 2H), 2.39 (s, 3H), 2.21 (s, 3H).

Example 866-(3,5-dimethylisoxazol-4-yl)-4-(6-methyl-2-(trifluoromethyl)quinolin-5-yl)-1H-benzo[d]imidazol-2(3H)-one

C₂₃H₁₇F₃N₄O₂. 439.2 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ 10.89 (s, 1H),10.39 (d, J=2.1 Hz, 1H), 8.16 (d, J=8.7 Hz, 1H), 7.98 (d, J=8.8 Hz, 1H),7.93 (d, J=8.8 Hz, 1H), 7.86 (d, J=8.8 Hz, 1H), 7.02 (d, J=1.4 Hz, 1H),6.84 (d, J=1.5 Hz, 1H), 2.41 (s, 3H), 2.32 (s, 3H), 2.24 (s, 3H).

Example 876-(3,5-dimethylisoxazol-4-yl)-4-(3-(trifluoromethyl)quinolin-4-yl)-1H-benzo[d]imidazol-2(3H)-one

C₂₂H₁₅F₃N₄O2. 425.2 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ 10.95 (s, 1H),10.54 (d, J=1.9 Hz, 1H), 9.29 (s, 1H), 8.24 (d, J=8.4 Hz, 1H), 7.96 (t,J=7.7 Hz, 1H), 7.67 (t, J=7.6 Hz, 1H), 7.47-7.37 (m, 1H), 7.06 (d, J=1.5Hz, 1H), 6.92 (d, J=1.6 Hz, 1H), 2.40 (s, 3H), 2.22 (s, 3H).

Example 884-(6-cyclopropylquinolin-5-yl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one

C₂₄H₂₀N₄O₂. 397.1 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ 10.83 (d, J=1.9 Hz,1H), 10.39 (d, J=2.1 Hz, 1H), 8.83-8.78 (m, 1H), 7.99 (d, J=8.9 Hz, 1H),7.64 (d, J=8.5 Hz, 1H), 7.41 (dd, J=8.6, 4.2 Hz, 1H), 7.34 (d, J=9.0 Hz,1H), 6.99 (d, J=1.5 Hz, 1H), 6.82 (d, J=1.5 Hz, 1H), 2.41 (s, 3H), 2.23(s, 3H), 1.80-1.73 (m, 1H), 0.86 (t, J=6.8 Hz, 4H).

Example 896-(3,5-dimethylisoxazol-4-yl)-4-(3-methylquinolin-4-yl)-1H-benzo[d]imidazol-2(3H)-one

C₂₂H₁₈N₄O₂. 371.1 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ 10.95 (d, J=1.9 Hz,1H), 10.49 (d, J=2.0 Hz, 1H), 9.09 (s, 1H), 8.15 (d, J=8.4 Hz, 1H), 7.84(t, J=7.8 Hz, 1H), 7.62 (t, J=7.5 Hz, 1H), 7.49 (d, J=8.4 Hz, 1H), 7.05(d, J=1.5 Hz, 1H), 6.87 (d, J=1.5 Hz, 1H), 2.41 (s, 3H), 2.29 (s, 3H),2.24 (s, 3H).

Example 906-(3,5-dimethylisoxazol-4-yl)-4-(3-methylcinnolin-4-yl)-1H-benzo[d]imidazol-2(3H)-one

C₂₁H₁₇N₅O₂. 372.1 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ 10.97 (s, 1H),10.55 (d, J=2.0 Hz, 1H), 8.62-8.41 (m, 1H), 7.97-7.85 (m, 1H), 7.78(ddd, J=8.4, 6.9, 1.4 Hz, 1H), 7.47 (d, J=8.5 Hz, 1H), 7.15-7.02 (m,1H), 6.95 (d, J=1.5 Hz, 1H), 2.69 (s, 3H), 2.42 (s, 3H), 2.25 (s, 3H).

Example 916-(3,5-dimethylisoxazol-4-yl)-4-(3-fluoro-6-methoxyquinolin-5-yl)-1H-benzo[d]imidazol-2(3H)-one

C₂₂H₁₇FN₄O₃. 405.1 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ 10.80 (d, J=2.0Hz, 1H), 10.41 (s, 1H), 8.79 (d, J=2.7 Hz, 1H), 8.17 (d, J=9.4 Hz, 1H),7.77 (d, J=9.4 Hz, 1H), 7.50-7.41 (m, 1H), 7.00-6.90 (m, 1H), 6.88-6.76(m, 1H), 3.89 (s, 3H), 2.41 (s, 3H), 2.24 (s, 3H). ¹⁹F NMR (376 MHz,DMSO-d₆) δ −128.19 (d, J=10.8 Hz).

Example 926-(3,5-dimethylisoxazol-4-yl)-4-(2,6-dimethylquinolin-5-yl)-1H-benzo[d]imidazol-2(3H)-one

C₂₃H₂₀N₄O₂. 385.1 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ 10.94 (s, 1H),10.40 (d, J=1.9 Hz, 1H), 8.11 (d, J=8.5 Hz, 2H), 7.99 (d, J=8.8 Hz, 1H),7.68 (d, J=8.7 Hz, 1H), 7.03 (d, J=1.6 Hz, 1H), 6.82 (d, J=1.5 Hz, 1H),2.85 (s, 3H), 2.41 (s, 3H), 2.31 (s, 3H), 2.24 (s, 3H).

Example 934-(3-chloroquinolin-4-yl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one

C₂₁H₁₅ClN₄O2. 391.1 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ 10.95 (d, J=1.9Hz, 1H), 10.61 (s, 1H), 9.03 (s, 1H), 8.22-8.02 (m, 1H), 7.91-7.77 (m,1H), 7.69-7.58 (m, 1H), 7.47 (d, J=8.4 Hz, 1H), 7.06 (d, J=1.5 Hz, 1H),6.92 (d, J=1.6 Hz, 1H), 2.42 (s, 3H), 2.24 (s, 3H).

Example 944-(6-(difluoromethoxy)quinolin-5-yl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one

C₂₂H₁₆F₂N₄O₃. 423.1 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ 10.86 (s, 1H),10.50 (s, 1H), 8.98-8.92 (m, 1H), 8.22 (d, J=9.3 Hz, 1H), 7.86 (d, J=8.6Hz, 1H), 7.80 (d, J=9.2 Hz, 1H), 7.58-7.51 (m, 1H), 7.23 (dd, J=74.5,72.9 Hz, 1H), 7.04-6.98 (m, 1H), 6.87 (d, J=1.6 Hz, 1H), 2.41 (s, 3H),2.24 (s, 3H).

Example 954-(3-chloro-8-fluoroquinolin-4-yl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one

C₂₁H₁₄ClFN₄O₂. 409.1 (M+1). ¹H NMR (400 MHz, DMSO-d6) δ 10.95 (d, J=2.0Hz, 1H), 10.58 (d, J=2.0 Hz, 1H), 9.08 (s, 1H), 7.73-7.47 (m, 2H),7.34-7.21 (m, 1H), 7.15-7.00 (m, 1H), 6.94 (t, J=1.3 Hz, 1H), 2.42 (s,3H), 2.24 (s, 3H).

Example 966-(3,5-dimethylisoxazol-4-yl)-4-(2-methylbenzo[d]thiazol-7-yl)-1H-benzo[d]imidazol-2(3H)-one

C₂₀H₁₆N₄O₂S. 377.1 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ 10.91 (d, J=2.2Hz, 1H), 10.68 (d, J=2.0 Hz, 1H), 7.95 (dd, J=8.0, 1.1 Hz, 1H), 7.59 (t,J=7.8 Hz, 1H), 7.50 (dd, J=7.4, 1.1 Hz, 1H), 7.09-7.01 (m, 1H),7.00-6.92 (m, 1H), 2.80 (s, 3H), 2.43 (s, 3H), 2.26 (s, 3H).

Example 976-(3,5-dimethylisoxazol-4-yl)-4-(2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-1H-benzo[d]imidazol-2(3H)-one

C₂₀H₁₇N₅O₂. 360.2 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ 11.73 (s, 1H),10.75 (d, J=1.8 Hz, 1H), 10.40 (d, J=1.8 Hz, 1H), 8.14 (dd, J=4.7, 1.6Hz, 1H), 7.64 (d, J=7.8 Hz, 1H), 7.02 (dd, J=7.8, 4.7 Hz, 1H), 6.86 (m,2H), 2.42 (s, 3H), 2.37 (s, 3H), 2.25 (s, 3H).

Example 986-(3,5-dimethylisoxazol-4-yl)-4-(6-methyl-1,7-naphthyridin-5-yl)-1H-benzo[d]imidazol-2(3H)-one

C₂₁H₁₇N₅O₂. 372.1 (M+1). ¹H NMR (400 MHz, DMSO-4%) 10.93 (d, J=1.9 Hz,1H), 10.48 (d, J=1.9 Hz, 1H), 9.52 (s, 1H), 9.06 (dd, J=4.0, 1.7 Hz,1H), 7.86-7.67 (m, 2H), 7.03 (d, J=1.6 Hz, 1H), 6.89 (d, J=1.6 Hz, 1H),2.48 (s, 3H), 2.41 (s, 3H), 2.24 (s, 3H).

Example 996-(3,5-dimethylisoxazol-4-yl)-4-(8-methoxy-3-methylquinolin-4-yl)-1H-benzo[d]imidazol-2(3H)-one

C₂₃H₂₀N₄O₃. 401.1 (M+1). ¹H NMR (400 MHz, DMSO-d6) δ 10.87 (s, 1H),10.69-10.18 (m, 1H), 8.81 (s, 1H), 7.38 (s, 1H), 7.13 (s, 1H), 7.01 (d,J=5.0 Hz, 1H), 6.90 (d, J=7.4 Hz, 1H), 6.79 (d, J=4.9 Hz, 1H), 3.97 (s,3H), 2.41 (s, 3H), 2.23 (d, J=4.8 Hz, 6H).

Example 1004-(3-chloro-2-methylquinolin-4-yl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one

C22H₁₇ClN₄O2. 405.1 (M+1). ¹H NMR (400 MHz, DMSO-6) δ 10.90 (s, 1H),10.55 (s, 1H), 8.04 (s, 1H), 7.76 (s, 1H), 7.52 (s, 1H), 7.37 (s, 1H),7.05 (s, 1H), 6.89 (s, 1H), 2.81 (s, 3H), 2.42 (s, 3H), 2.25 (d, J=4.1Hz, 3H).

Example 101 6-(3,5-dimethylisoxazol-4-yl)4-(3-ethyl-2-methylquinolin-4-yl)-1H-benzo[d]imidazol-2(3H)-one

C₂₄H₂₂N₄O₂. 399.2 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ 10.86 (s, 1H),10.43 (s, 1H), 7.95 (s, 1H), 7.63 (s, 11H), 7.40 (d, J=8.8 Hz, 1H), 7.17(d, J=8.2 Hz, 1H), 7.01 (s, 1H), 6.81 (s, 1H), 2.76 (s, 5H), 2.41 (s,3H), 2.23 (s, 3H), 1.00 (d, J=7.8 Hz, 3H).

Example 1024-(6-(3,5-dimethylisoxazol-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-3-methylquinoline-8-carbonitrile

C23H₁₇N₅O₂. 396.1 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ 10.93 (d, J=1.8 Hz,1H), 10.45 (d, J=1.9 Hz, 1H), 9.10 (s, 1H), 8.31 (dd, J=6.9, 1.6 Hz,1H), 7.88-7.51 (m, 2H), 7.16-6.92 (m, 1H), 6.88 (d, J=1.6 Hz, 1H), 2.41(s, 3H), 2.30 (s, 3H), 2.24 (s, 3H).

Example 1034-(3-(difluoromethyl)quinolin-4-yl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one

C₂₇H₁₆F₂N₄O₂. 407.1 (M+1). ¹H NMR (400 MHz, DMSO-6) δ 10.96 (d, J=1.8Hz, 1H), 10.54 (d, J=1.9 Hz, 1H), 9.22 (s, 1H), 8.19 (dd, J=8.5, 1.2 Hz,1H), 8.06-7.78 (m, 1H), 7.64 (ddd, J=8.3, 6.8, 1.3 Hz, 1H), 7.54-7.35(m, 1H), 7.08 (d, J=1.6 Hz, 1H), 7.05-6.67 (m, 2H).

Example 1044-(3,5-dimethylisoxazol-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)cinnoline-3-carboxylicacid

A mixture of 6-(3,5-dimethylisoxazol-4-yl)4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2(3H)-one(100.0 mg, 0.282 mmol) and methyl 4-chlorocinnoline-3-carboxylate (94.0mg, 0.422 mmol) was treated with PdCl₂dppf-CH₂Cl₂ (20.6 mg, 0.028 mmol)in the presence of 1,8-Diazabicycloundec-7-ene (DBU, 300.0 mg, 1.971mmol, 7.0 equiv) in DMSO (1 mL) and water (1 mL). The reaction mixturewas heated at 110° C. for 12 min in oil bath. The reaction mixture waspurified by HPLC to give4-(6-(3,5-dimethylisoxazol-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)cinnoline-3-carboxylicacid.

C₂₁H₁₅N₅SO₄. MS. m/z 402.0 (M+1). ¹H NMR (400 MHz, Methanol-d₄) δ 8.67(d, J=8.8 Hz, 1H), 8.09 (t, J=8.8 Hz, 1H), 7.92 (d, J=8.8 Hz, 1H), 7.70(di, J=8.8 Hz, 1H), 7.17 (s, 1H), 6.96 (s, 1H), 2.44 (s, 3H), 2.29 (s,3H).

Example 1056-(3,5-dimethylisoxazol-4-yl)-4-(3-methylisoquinolin-4-yl)-1H-benzo[d]imidazol-2(3H)-one

6-(3,5-Dimethylisoxazol-4-yl)-4-(3-methylisoquinolin-4-yl)-1H-benzo[d]imidazol-2(3H)-onewas prepared from 4-iodo-3-methylisoquinoline in a similar fashion asExample 104.

C₂₂H₁₈N₄O₂. MS. m/z 371.1 (M+1). ¹H NMR (400 MHz, Methanol-d₄) 9.26 (s,1H), 8.16 (d, J=7.7 Hz, 1H), 7.67 (m, 2H), 7.42 (d, J=8.2 Hz, 1H) 7.15(s, 1H), 6.91 (s, 1H), 2.50 (s, 3H), 2.45 (s, 3H), 2.29 (s, 3H).

Example 1066-(3,5-dimethylisoxazol-4-yl)-4-(2-methylnaphthalen-1-yl)-1H-benzo[d]imidazol-2(3H)-one

In a 2-5 mL Smith Process Vial,6-(3,5-dimethylisoxazol-4-yl)-4-iodo-1H-benzo[d]imidazol-2(3H)-one(100.0 mg 0.282 mmol), (2-methylnaphthalen-1-yl)boronic acid (176.0 mg,0.946 mmol, 3.36 equiv), PEPPSI-iPr (19.2 mg, 0.028 mmol, 0.1 equiv) andCs₂CO₃ (337.0 mg, 1.126 mmol, 4 equiv) were placed. The mixture wassuspended in 1,4-dioxane (1.5 mL) and water (0.5 mL) under N2. Themixture was heated at 150° C. for 75 min using microwave reactor(Biotage Optimizer). After an aqueous work up, the crude product waspurified by a silica-gel column chromatography (hexane/EtOAc 20:80) togive6-(3,5-dimethylisoxazol-4-yl)-4-(2-methylnaphthalen-1-yl)-1H-benzo[d]imidazol-2(3H)-one.

C23H19N302. MS. m/z 370.1 (M+1). 1H NMR (400 MHz, Methanol-d4) δ 7.88(d, J=8.6 Hz, 2H), 7.50 (d, J=8.6 Hz, 1H), 7.45-7.38 (m, 1H), 7.38-7.33(m, 2H), 7.10 (s, 1H), 6.82 (s, 1H), 2.43 (s, 3H), 2.28 (s, 6H).

Example 1074-(2-(difluoromethyl)-3-methylquinolin-4-yl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one

4-(2-(Difluoromethyl)-3-methylquinolin-4-yl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-onewas prepared from 2-(difluoromethyl)-4-iodo-3-methylquinoline in asimilar fashion as Example 104.

C₂₃H₁₈F₂N₄O₂. MS. m/z 421.1 (M+1). ¹H NMR (400 MHz, Methanol-d4) δ 8.18(d, J=9.0 Hz, 1H), 7.83-7.74 (m, 1H), 7.63-7.57 (m, 1H), 7.45 (d, J=9.4Hz, 1H), 7.23-6.87 (m, 2H), 2.44 (s, 6H), 2.30 (s, 3H).

Example 1084-chlor-5-(3,5-dimethylisoxazol-4-yl)-7-(6-methylquinolin-5-yl)-1H-benzo[d]imidazol-2(3H)-one

In 0.5-2 mL Smith Process Vial, the substrate (25.0 mg, 0.067 mmol) andNCS (36.3 mg, 0.135 mmol) were dissolved into THF (2 mL). The mixturewas heated at 80° C. for 2 h in an oil bath. The reaction mixture waspurified by HPLC (5-95% acetonitrile:water with 0.05% trifluoroaceticacid, on a Phenomenex Luna C18 column) to give the desired product.

C₂₂H₁₇ClN₄O₂. MS. m/z 405.1 (M+1), 407.1 (M+2+1). ¹H NMR (400 MHz,Methanol-d₄) δ 9.25-9.05 (d, J=5.8 Hz, 1H), 8.47-8.40 (m, 1H), 8.30 (d,J=9.0 Hz, 1H), 8.20 (d, J=9.0 Hz, 1H), 7.96-7.90 (m, 1H), 7.19 (s, 1H),2.40 (s, 3/2H), 2.39 (s, 3/2H), 2.38 (s, 3/2H), 2.34 (s, 3/2H) 2.21 (s,3/2H), 2.19 (s, 3/2H).

Example 1096-(3,5-dimethylisoxazol-4-yl)-4-(8-fluoro-6-methylquinolin-5-yl)-1H-benzo[d]imidazol-2(3H)-oneStep 1

3,5-Dicyclopropylisoxazole (70.0 mg, 0.469 mmol) was treated with NBS(167.0 mg, 0.938 mmol, 2 equiv) in CH2Cl2 at room temperature for 12 h.The solvent was removed under a reduced pressure and the residue wasdirectly loaded onto a silica gel column chromatography (hexane EtOAc87:13) to give 5-bromo-8-fluoro-6-methylquinoline.

C9H10BrON. MS. m/z 239.9 (M−1+1), 241.9 (M+1+1).

C₂₂H₁₇FN₄O₂. MS. m/z 398.1 (M+1). ¹H NMR (400 MHz, Methanol-d₄) δ 8.93(d, 1H, J=4.0 Hz), 8.08 (d, 1H, J=8.0 Hz), 7.70 (d, 1H, J=11.2 Hz), 7.67(dd, 1H, J=8.0, 4.0 Hz), 7.15 (d, 1H, J=1.0 Hz), 6.88 (d, 1H, J=1.0 Hz),2.43 (s, 3H), 2.38 (s, 3H), 2.28 (s, 3H).

Example 110 Example 111, and Example 1127-(3,5-demethyl-1H-pyrazol-4-yl)-5-(3,5-dimethyloxazol-4-yl)-1-methyl-1H-benzo[d]imidazol-2(3H)-one

5-(3,5-dimethylisoxazol-4-yl)-7-iodo-1-methyl-1H-benzo[d]imidazol-2(3H)-one(60 mg, 0.16 mmol) was placed in a microwave vial followed by theaddition of PEPPSI (11 mg, 0.016 mmol) and cesium carbonate (158.9 mg,4.9 mmol). The material was then dissolved in 1.5 mL of DME and 1.5 mLof water. The vial was then placed in the microwave where it was heatedto 165° C. for one hour. The crude solution was then diluted with waterand extracted 3 times with ethyl acetate. Combined organic layers werewashed with brine, dried over sodium sulphate, filtered, concentrated invacuo, and purified via HPLC to afford7-(3,5-dimethyl-1H-pyrazol-4-yl)-5-(3,5-dimethylisoxazol-4-yl)-1-methyl-1H-benzo[d]imidazol-2(3H)-one.

C₁₈H₁₉NO₂; 338.2 (m/z+1). ¹H NMR (400 MHz, cd₃od) δ 7.03 (d, J=1.6 Hz,1H), 6.75 (d, J=1.6 Hz, 1H), 3.01 (s, 3H), 2.41 (s, 3H), 2.26 (s, 3H),2.12 (s, 6H).

Example 1136-(3,5-dimethylisoxazol-4-yl)-4-(1-(4-fluorophenyl)vinyl)-1H-benzo[d]imidazol-2(3H)-one

6-(3,5-Dimethylisoxazol-4-yl)-4-iodo-1H-benzo[d]imidazol-2(3H)-one (100mg, 0.28 mmol), 1-(4-Fluorophenyl)vinylboronic acid, pinacol ester(209.59 mg, 0.84 mmol), PEPPSI″-IPr catalyst (19.19 mg, 0.03 mmol),1,8-Diazabicyclo[5.4.0]undec-7-ene solution (0.25 ml, 1.69 mmol) weremixed in 1-Methyl-2-pyrrolidinone (6 ml) and Water (3 ml) in sealed in amicrowave vial and heated to 110° C. for 30 minutes in a microwavereactor. The reaction mixture was then cooled and partitioned betweenwater and ethyl acetate. The organic layer was washed with water thenbrine and dried over sodium sulfate. Purification on silica gel(Hexane/EtOAc) followed by preparative HPLC afforded6-(3,5-dimethylisoxazol-4-yl)-4-(1-(4-fluorophenyl)vinyl)-1H-benzo[d]imidazol-2(3H)-one.

C20H16FN3O2; 350.2 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 7.35 (dd, J=8.7,5.6 Hz, 2H), 7.16 (t, J=8.8 Hz, 2H), 6.86 (d, J=1.6 Hz, 1H), 6.59 (d,J=1.6 Hz, 1H), 5.81 (s, 1H), 5.44 (s, 1H), 2.32 (s, 3H), 2.14 (s, 3H).19F NMR (376 MHz, DMSO-d6) δ −114.96 (ddd, J=14.4, 9.1, 5.5 Hz).

The following compound(s) were made in a similar fashion usingappropriately substituted boronic acids or esters.

Example 1146-(3,5-dimethyloxazol-4-yl)-4-(2-(morpholinomethyl)phenyl)-1H-benzo[d]imidazol-2(3H)-one

C₂₃H₂₄N₄O₃; 405.2 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 7.52 (dd, J=7.4,1.7 Hz, 1H), 7.40 (dtd, J=14.7, 7.3, 1.7 Hz, 2H), 7.30 (dd, J=7.2, 1.8Hz, 1H), 6.90 (d, J=1.6 Hz, 1H), 6.78 (d, J=1.6 Hz, 1H), 3.47 (t, J=4.4Hz, 3H), 2.41 (s, 3H), 2.24 (s, 5H), 1.66 (d, J=5.6 Hz, 1H), 1.54 (dq,J=13.7, 6.9, 6.3 Hz, 2H).

Example 1156-(3,5-dimethyloxazol-4-yl)-4-(1-(4-fluorophenyl)ethyl)-1H-benzo[d]imidazol-2(3H)-one

A suspension of6-(3,5-dimethylisoxazol-4-yl)-4-(1-(4-fluorophenyl)vinyl)-1H-benzo[d]imidazol-2(3H)-one(60 mg, 0.172 mmol) and 10% palladium on carbon (20 mg) in 5 mL ethanolwas purged with hydrogen gas and allowed to stir for 2 hours. Thereaction mixture was then filtered and the solvents evaporated. Residuewas purified by preparative HPLC which afforded6-(3,5-dimethylisoxazol-4-yl)-4-(1-(4-fluorophenyl)ethyl)-1H-benzo[d]imidazol-2(3H)-one.

C₂₀H₁₈FN₃O₂; 352.2 (M+1). ¹H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H),10.71 (s, 1H), 7.45 (dd, J=8.6, 5.7 Hz, 2H), 7.12 (t, J=8.9 Hz, 2H),6.84 (d, J=1.5 Hz, 1H), 6.73 (d, J=1.5 Hz, 1H), 4.43 (q, J=7.2 Hz, 1H),2.35 (s, 3H), 2.17 (s, 3H), 1.61 (d, J=7.2 Hz, 3H). ¹⁹F NMR (376 MHz,DMSO-d6) δ −117.55 (tt, J=9.1, 5.6 Hz).

Example 1165-(3,5-dimethyloxazol-4-yl)-1-ethyl-7-(6-methylquinolin-5-yl)-1H-benzo[d]imidazol-2(3H)-one

Step 1

4-(3,5-Dimethylisoxazol-4-yl)-2-iodo-6-nitroaniline (4 g, 11.1 mmol) wasdissolved in 100 mL DCM and to the solution was added pyridine (2.7 mL,33.3 mmol) before cooling to 0° C. under argon. To the solution was thenadded dropwise triflic anhydride (3 g, 14.5 mmol) before allowing thereaction to slowly warm to room temperature overnight. The reactionmixture was suspended slowly into stirring DCM/water before extracting 3times with DCM. Organics were then washed with water, brine then driedover sodium sulfate. Solvent was removed under reduced pressure to yieldcrudeN-(4-(3,5-dimethylisoxazol-4-yl)-2-iodo-6-nitrophenyl)-2,2,2-trifluoroacetamideas a brown oil

Step 2

A mixture ofN-(4-(3,5-dimethylisoxazol-4-yl)-2-iodo-6-nitrophenyl)-2,2,2-trifluoroacetamide(2.2 g, 4.83 mmol), cesium carbonate (3.94 g, 12.08 mmol) andN,N-Dimethylformamide (100 ml) was stirred at room temperature underargon. To the mixture was added iodoethane (3.77 g, 24.17 mmol) andreaction was heated to 45° C. overnight. Crude mixture was diluted inEtOAc and water and extracted 3 times with EtOAc. Organics were washedwith water, aq LiCl, then brine, dried over sodium sulfate andevaporated to dryness under reduced pressure to afford crudeN-(4-(3,5-dimethylisoxazol-4-yl)-2-iodo-6-nitrophenyl)-N-ethyl-2,2,2-trifluoroacetamideas a dark oil.

Step 3

CrudeN-(4-(3,5-dimethylisoxazol-4-yl)-2-iodo-6-nitrophenyl)-N-ethyl-2,2,2-trifluoroacetamide(1.5 g, 3.1 mmol) was dissolved in 100 mL of methanol. To the mixturewas added 1M sodium methoxide in methanol (15.5 mL, 15.5 mmol) andreaction stirred at room temperature until complete. Reaction was thenquenched with 15 mL of 1M HCl or until pH is approximately neutral thendiluted with aqueous ammonium chloride. Methanol was removed underreduced pressure and then remaining suspension was extracted with EtOAc.The solution was washed with water, brine then dried over sodiumsulfate. Solvents were removed under reduced pressure the residue wasthen dissolved in 20 mL of ethanol and placed in a sealed pressure tubewith stannous chloride (2.2 g, 11.62 mmol). The mixture was heated at120° C. for 1 hour. Reaction mixture was cooled to room temperature. Tothe mixture was added 1M NaOH (10 mL) and the mixture was stirred atroom temperature for 30 minutes. At this point the reaction mixture wasdiluted with water and extracted with EtOAc (3 times). The solution waswashed with water, brine and dried over sodium sulfate. Solvents wereremoved under reduced pressure and crude product was purified by silicagel chromatography (Hexanes/EtOAc as the eluent) to provide4-(3,5-dimethylisoxazol-4-yl)-N1-ethyl-6-iodobenzene-1,2-diamine (310mg, 22%).

Step 4

4-(3,5-Dimethylisoxazol-4-yl)-N1-ethyl-6-iodobenzene-1,2-diamine (105mg, 0.29 mmol), 6-methylquinolin-5-ylboronic acid (274.86 mg, 1.47mmol), 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.26 mL, 1.76 mmol),1-Methyl-2-pyrrolidinone (5 mL), and water (2 mL) were placed inmicrowave vial, pre-stirred for 2 minutes, then heated to 110° C. for 15minutes. Reaction mixture was diluted with EtOAc and aqueous ammoniumchloride and extracted with EtOAc (3 times). Organics were washed withammonium chloride, water and brine and dried over sodium sulfate.Solvent was evaporated to dryness. Crude material was purified by silicagel chromatography (DCM/MeOH as eluent) to afford4-(3,5-dimethylisoxazol-4-yl)-N1-ethyl-6-(6-methylquinolin-5-yl)benzene-1,2-diamine.

Step 5

4-(3,5-Dimethylisoxazol-4-yl)-N1-ethyl-6-(6-methylquinolin-5-yl)benzene-1,2-diamine(90 mg, 0.24 mmol) and 1,1′-carbonyldiimidazole (86.2 mg, 0.53 mmol)were added to tetrahydrofuran (10 ml) in a sealed vessel and heated to105° C. overnight. The reaction mixture was the diluted in EtOAc andaqueous ammonium chloride and extracted with EtOAc (3 times). Organicswere washed with ammonium chloride, water and brine and dried oversodium sulfate. Solvent was evaporated to dryness Crude material waspurified by silica gel chromatography (DCM/MeOH as eluent) then bypreparative HPLC to afford5-(3,5-dimethylisoxazol-4-yl)-1-ethyl-7-(6-methylquinolin-5-yl)-1H-benzo[d]imidazol-2(3H)-one.

C₂₄H₂₂N₄O₂. 399.2 (M+1). 1H NMR (400 MHz, Methanol-d4) δ 8.86 (d, J=4.2Hz, 1H), 8.12 (d, J=8.7 Hz, 1H), 7.97-7.89 (m, 1H), 7.85 (d, J=8.7 Hz,1H), 7.51 (dd, J=8.6, 4.3 Hz, 1H), 7.19 (d, J=1.6 Hz, 1H), 6.82 (d,J=1.6 Hz, 1H), 3.19-3.00 (m, J=7.1 Hz, 2H), 2.43 (s, 3H), 2.36 (s, 3H),2.27 (s, 3H), 0.52 (t, J=7.1 Hz, 3H).

Example 1175-(3,5-dimethylisoxazol-4-yl)-7-(6-methylquinolin-5-yl)-1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazol-2(3H)-one

Step 1

4-Bromo-2-chloroaniline (5000 mg, 24.22 mmol) was dissolved intrifluoroacetic acid (40 ml) and 1,2-dimethoxyethane (50 ml) then cooledunder argon to 0° C. To the mixture was added 2-picoline borane complex(12951.34 mg, 121.08 mmol) and then the reaction mixture was heated 110°C. for 90 minutes. Solvents were removed under reduced pressure andcrude material was taken up in 1N HCl and stirred at 110° C. 30 minutes.Crude mixture was then diluted with EtOAc and water and extracted EtOAc(3 times). Organics were washed with water then brine, dried over sodiumsulfate and evaporated to dryness under reduced pressure. Crude materialwas purified by silica gel chromatography using EtOAc/Hexanes as theeluent to afford 4-bromo-2-chloro-N-(2,2,2-trifluoroethyl)aniline.

Step 2

A mixture of 4-Bromo-2-chloro-N-(2,2,2-trifluoroethyl)aniline (5280 mg,18.3 mmol), 3,5-dimethylisoxazole-4-boronic acid, pinacol ester (4082.76mg, 18.3 mmol), PEPPSI″-IPr catalyst (1247.24 mg, 1.83 mmol), Cesiumcarbonate (17889.52 mg, 54.91 mmol) in 120 mL DME:H₂O (2:1) was heatedto 90° C. under argon. The reaction mixture was then cooled andpartitioned between water and ethyl acetate. The organic layer waswashed with water then brine and dried over sodium sulfate. Purificationon silica gel (Hexanes/EtOAc) afforded2-chloro-4-(3,5-dimethylisoxazol-4-yl)-N-(2,2,2-trifluoroethyl)aniline.

Step 3

2-Chloro-4-(3,5-dimethylisoxazol-4-yl)-N-(2,2,2-trifluoroethyl)aniline(200 mg, 0.66 mmol) was dissolved in dichloromethane (10 mL) andacetonitrile (10 mL) and cooled to 0° C. under argon. To reactionmixture was added 0.5M nitronium tetrafluoroborate (1.84 ml) slowly over20 minutes. Reaction mixture was stirred at 0° C., for 1 hour andallowed to warm to room temperature. After 3 hours, the reaction mixturewas cooled to 0° C. again and 0.5M nitronium tetrafluoroborate insulfolane (1.84 ml) was added and the reaction solution was stirred atroom temperature overnight. Reaction solvents were removed under reducedpressure and the residue taken up in EtOAc and the solution was washedwith aq. NaHCO₃, then water, brine and dried over sodium sulfate.Solvents were removed under reduced pressure to yield a dark redoil/liquid. This material was dissolved in 2 mL of ethanol and 2 mL ofacetic acid. To the solution was added Zinc dust and suspension wasstirred. After 30 minutes of stirring the zinc dust was filtered off andthe solvents were removed under reduced pressure. The residue wasdissolved in EtOAc and the solution was washed with aq. NaHCO₃, thenwater, brine and dried over sodium sulfate. Solvent was removed and thecrude residue was purified by silica gel chromatography (Hexanes/EtOAcas the eluent) to afford6-chloro-4-(3,5-dimethylisoxazol-4-yl)-N1-(2,2,2-trifluoroethyl)benzene-1,2-diamineas a light colored oil.

Example 118

The following compound was synthesized in a similar fashion as that ofExample 117.

C₂₄H₁₉F₃N₄O₂; 453.3 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.51 (s, 1H),8.86 (dd, J=4.2, 1.6 Hz, 1H), 8.16-7.97 (m, 1H), 7.78 (d, J=8.7 Hz, 1H),7.73-7.61 (m, 1H), 7.44 (dd, 3-8.6, 4.2 Hz, 1H), 7.14 (d, J=1.7 Hz, 1H),6.81 (d, J=1.7 Hz, 1H), 3.89-3.58 (m, 2H), 2.39 (s, 3H), 2.22 (d, J=4.6Hz, 6H). 19F NMR (376 MHz, DMSO-d6) δ −69.65 (t, J=8.9 Hz).

Example 1195-(3,5-dimethylisoxazol-4-yl)-1-methyl-7-(6-methylquinolin-5-yl)-H-benzo[d]imidazol-2(3H)-oneStep 1: 4-(3,5-dimethylisoxazol-4-yl)-2-iodo-N-methyl-6-nitroaniline

To a flask containing4-(3,5-dimethylisoxazol-4-yl)-2-iodo-6-nitroaniline (1000 mg, 2.78 mmol,1 equiv) was added DMF (15 mL, 0.2 M), cesium carbonate (1.4 gm, 4.17mmol, 1.5 equiv.) and iodomethane (260 μL, 4.17 mmol, 1.5 equiv). Afteran hour, the reaction was quenched with water and partitioned betweenwater and ethyl acetate. The organic layer was washed with brine anddried over sodium sulfate. Purification was carried out by flash columnchromatography to furnish4-(3,5-dimethylisoxazol-4-yl)-2-iodo-N-methyl-6-nitroaniline (615 mg,60%). ¹H NMR (400 MHz, cdcl₃) δ 7.81 (t, J=3.0 Hz, 1H), 7.70 (d, J=2.1Hz, 1H), 2.97 (s, 3H), 2.40 (d, J=16.8 Hz, 3H), 2.26 (d, J=14.2 Hz, 3H).

LCMS (m/z+1) 373.

Step 2:5-(3,5-dimethylisoxazol-4-yl)-1-methyl-7-(6-methylquinolin-5-yl)-1H-benzo[d]imidazol-2(3H)-one

To a microwave vial containing4-(3,5-dimethylisoxazol-4-yl)-2-iodo-N-methyl-6-nitroaniline (610 mg,1.64 mmol, 1 equiv) was added EtOH (12 mL, 0.25M) and tin (II) chloride(622 mg, 3.28 mmol, 2 equiv). The reaction mixture was heated for 30 minat 110° C. The reaction was then stirred in 2N NaOH solution for 20minutes and partitioned between water and ethyl acetate. The organiclayer was washed with brine and dried over sodium sulfate. Purificationwas carried out by flash column chromatography to furnish4-(3,5-dimethylisoxazol-4-yl)-6-iodo-N1-methylbenzene-1,2-diamine.

LCMS (m/z+1) 344.02

Step 3:5-(3,5-dimethylisoxazol-4-yl)-7-iodo-1-methyl-1H-benzo[d]imidazol-2(3)-one

To a flask containing4-(3,5-dimethylisoxazol-4-yl)-6-iodo-N1-methylbenzene-1,2-diamine (299mg, 0.87 mmol, 1 equiv) was added THF (8 mL) and CDI (282 mg, 1.74 mmol,2 equiv). The reaction mixture was heated for 2 hr at 120 OC. Thereaction mixture was then concentrated in vacuo and the solid trituratedwith diethyl ether to furnish5-(3,5-dimethylisoxazol-4-yl)-7-iodo-1-methyl-1H-benzo[d]imidazol-2(3H)-oneas a light yellow solid.

LCMS (m/z+1) 370.00.

To a microwave vial containing5-(3,5-dimethylisoxazol-4-yl)-7-iodo-1-methyl-1H-benzo[d]imidazol-2(3H)-one(40 mg, 0.11 mmol, 1 equiv.) were added 3,5-6-methylquinolin-5-ylboronicacid (51 mg, 0.27 mmol, 2.5 equiv.), Cs₂CO₃ (141 mg, 0.43 mmol, 4equiv.) and PEPPSI™-IPr catalyst (8 mg, 0.02 mmol, 0.1 equiv.) inDME-H₂O (20 mL, 0.2 M, 2/1, v/v). The mixture was heated to 140° C.After 2 hr, the reaction was complete. Following cooling, the reactionmixture was extracted with EtOAc and washed with water, saturated NH₄Cl.After drying with MgSO₄, it was filtered and concentrated to drynessunder reduced pressure. Purification was carried out by reverse phaseHPLC to furnish the title compound.

¹H NMR (400 MHz, cd₃od) δ 8.82 (d, J=4.3 Hz, 1H), 8.09 (d, J=8.7 Hz,1H), 7.82 (t, J=7.1 Hz, 2H), 7.47 (dd, J=8.5, 4.3 Hz, 1H), 7.17 (d,J=1.6 Hz, 1H), 6.82 (d, J=1.6 Hz, 1H), 2.53 (s, 3H), 2.42 (s, 3H), 2.33(s, 3H), 2.27 (s, 3H). LCMS (m/z+1) 385.23.

Example 1207-(1,4-dimethyl-1H-pyrazol-5-yl)-5-(3,5-dimethyloxazol-4-yl)-1-methyl-1H-benzo[d]imidazol-2(3H)-one

To a microwave vial containing5-(3,5-dimethylisoxazol-4-yl)-7-iodo-1-methyl-1H-benzo[d]imidazol-2(3H)-one(40 mg, 0.11 mmol, 1 equiv.) were added1,4-dimethyl-1H-pyrazol-5-ylboronic acid (72 mg, 0.32 mmol, 3 equiv.),Cs₂CO₃ (141 mg, 0.43 mmol, 4 equiv.) and PEPPSI™-IPr catalyst (8 mg,0.02 mmol, 0.1 equiv.) and DME-H₂O (20 mL, 0.2 M, 2/1, v/v). The mixturewas heated to 140° C. After 1 hr, the reaction was complete. Followingcooling, the reaction was extracted with EtOAc and the organic solutionwas washed with water, saturated NH₄Cl. After drying with MgSO₄, it wasfiltered and concentrated to dryness under reduced pressure.Purification of the residue was carried out by reverse phase HPLC tofurnish the desired product.

1H NMR (400 MHz, cd3od) δ 7.44 (s, 1H), 7.15 (d, J=1.6 Hz, 1H), 6.88 (d,J=1.6 Hz, 1H), 3.65 (s, 3H), 0.90 (a, 3H), 2.42 (s, 3H), 2.27 (s, 7H),1.95 (s, 3H). LCMS (m/z+1) 338.19.

Example 1215,7-bis(3,5-dimethylisoxazol-4-yl)-1-methyl-1H-benzo[d]imidazol-2(3H)-one

To a microwave vial containing5-(3,5-dimethylisoxazol-4-yl)-7-iodo-1-methyl-1H-benzo[d]imidazol-2(3H)-one(40 mg, 0.11 mmol, 1 equiv.) were added 3,5-dimethylisoxazole-4-boronicacid pinacol ester (72 mg, 0.32 mmol, 3 equiv.), Cs₂CO₃ (141 mg, 0.43mmol, 4 equiv.), PEPPSI™-IPr catalyst (8 mg, 0.02 mmol, 0.1 equiv.) andDME-H₂O (20 mL, 0.2 M, 2/1, v/v). The mixture was heated to 140° C.After 1 hr, the reaction was complete. Following cooling, the reactionmixture was extracted with EtOAc and the organic solution was washedwith water, saturated NH₄Cl. After drying with MgSO₄, it was filteredand concentrated to dryness. The resulting solid was washed with EtOAc.Purification of the residue was carried out by reverse phase HPLC tofurnish the title compound.

¹H NMR (400 MHz, cd₃od) δ 7.09 (d, J=1.6 Hz, 1H), 6.81 (d, J=1.6 Hz, 1H)3.11 (d, J=14.5 Hz, 3H), 2.41 (s, 3H), 2.35-2.23 (m, 6H), 2.15 (s, 3H).LCMS (m/z+1) 339.15.

Example 1226-(3,5-dimethylisoxazol-4-yl)-4-(1-ethyl-4-methyl-1H-pyrazol-5-yl)-4H-benzo[d]imidazol-2(3H)-one

To a microwave vial containing6-(3,5-dimethylisoxazol-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2(3H)-one(40 mg, 0.11 mmol, 1 equiv.) were added5-bromo-1-ethyl-4-methyl-1H-pyrazole 11 (64 mg, 0.34 mmol, 3 equiv.),Pd(dppf)Cl₂. CH₂Cl₂ (9 mg, 0.011 mmol, 0.1 equiv.), DBU (101 μL, 6equiv.) and DMSO-H₂O (4 mL, 0.2 M, 2/1, v/v). The mixture was heated to120° C. for 30 min in microwave. The reaction was concentrated underreduced pressure and purification was carried out by reverse phase HPLC.

1H NMR (400 MHz, Methanol-d4) S7.45 (d, J=0.8 Hz, 1H), 7.09 (d, J=1.6Hz, 1H), 6.88 (d, J=1.6 Hz, 1H), 4.02 (dd, J=28.3, 7.2 Hz, 1H), 2.43 (s,4H), 2.27 (s, 4H), 1.96 (d, J=0.7 Hz, 3H), 1.25 (t, J=7.2 Hz, 4H). LCMS(m/z+1) 338.22.

Example 1235-(6-(3,5-dimethylisoxazol-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-1-methyl1H-pyrazole-4-carboxamide

To a microwave vial containing6-(3,5-dimethylisoxazol-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2(3H)-one(100 mg, 0.28 mmol, 1 equiv.) was added5-bromo-1-methyl-1H-pyrazole-4-carbonitrile (130 mg, 0.30 mmol, 2.5equiv.), Pd(dppf)Cl₂.CH₂Cl₂ (23 mg, 0.03 mmol, 0.1 equiv.) and DBU (253μL, 1.69 mmol, 6 equiv.) and dissolved in DMSO-H₂O (4 mL, 0.2 M, 2/1,v/v). The mixture was heated to 120° C. for 30 min in microwave. Thereaction was concentrated in vacuo and purification was then carried outby reverse phase HPLC.

LCMS (m/z+1) 352.99. 1H NMR (400 MHz, Methanol-d4) δ 8.04 (s, 1H), 7.10(d, J=1.6 Hz, 1H), 6.95 (d, J=1.6 Hz, 1H), 3.72 (s, 4H), 2.40 (d, J=15.8Hz, 4H), 2.25 (d, J=16.4 Hz, 4H).

Example 1241-cyclopropyl-5-(3,5-dimethyloxazol-4-yl)-7-(6-methylquinolin-5-yl)-1H-benzo[d]imidazol-2(3H)-oneStep 1:5-(3,5-dimethylisoxazol-4-yl)-7-iodo-1-methyl-1H-benzo[d]imidazol-2(3H)-one

To a mixture of4-(3,5-dimethylisoxazol-4-yl)-6-iodo-N1-methylbenzene-1,2-diamine (1.89g, 5.5 mmol, 1 equiv.) in a pressure tube was added THF (5 mL) and CDI(2.67 g, 18.5 mmol, 3 equiv.). The mixture was heated to 120° C. for 30minutes in a microwave reactor. The reaction was concentrated in vacuoand purified by HPLC to provide5-(3,5-dimethylisoxazol-4-yl)-7-iodo-1-methyl-1H-benzo[d]imidazol-2(3H)-one.

LCMS (m/z+1) 370.16.

Step 2:N-cyclopropyl-4-(3,5-dimethylisoxazol-4-yl)-2-iodo-6-nitroaniline

To a mixture of 4-(4-bromo-3-iodo-5-nitrophenyl)-3,5-dimethylisoxazole(1 g, 2.36 mmol, 1 equiv.) in a pressure tube was added NMP (10 mL) andcyclopropylamine (982 μL, 14.2 mmol, 6 equiv.). The mixture was heatedto 130° C. for 60 minutes in a microwave reactor. The reaction wasconcentrated under reduced pressure and purified by flash columnchromatography to provideN-cyclopropyl-4-(3,5-dimethylisoxazol-4-yl)-2-iodo-6-nitroaniline.

LCMS (m/z+1) 400.02

Step 3:1-cyclopropyl-5-(3,5-dimethylisoxazol-4-yl)-7-iodo-1H-benzo[d]imidazol-2(3H)-one

To a mixture ofN1-cyclopropyl-4-(3,5-dimethylisoxazol-4-yl)-6-iodobenzene-1,2-diamine(170 mg, 0.46 mmol, 1 equiv.) in a pressure tube was added THF (5 mL)and CDI (223 mg, 1.38 mmol, 3 equiv.). The mixture was heated to 120° C.for 30 minutes in a microwave reactor. The reaction was concentrated invacuo and purified by HPLC to provide1-cyclopropyl-5-(3,5-dimethylisoxazol-4-yl)-7-iodo-1H-benzo[d]imidazol-2(3H)-oneLCMS (m/z+1) 396.3.

Step 4

To a microwave vial containing1-cyclopropyl-5-(3,5-dimethylisoxazol-4-yl)-7-iodo-1H-benzo[d]imidazol-2(3H)-one(25 mg, 0.063 mmol, 1 equiv.) was added 3,5-6-methylquinolin-5-ylboronicacid (71 mg, 0.38 mmol, 6 equiv.), Pd(dppf)C₂.CH₂Cl₂ (11 mg, 0.013 mmol,0.1 equiv.) and DBU (76 μL, 0.51 mmol, 8 equiv.) and dissolved inDMSO-H2O (4 mL, 0.2 M, 2/1, v/v). The mixture was heated to 140° C. for30 minutes in the microwave reactor. Purification was carried out byreverse phase HPLC.

1H NMR (400 MHz, Methanol-d4) δ 8.80 (dd, J=4.4, 1.6 Hz, 1H), 8.10-7.98(m, 1H), 7.93 (dd, J=8.6, 1.3 Hz, 1H), 7.79 (d, J=8.7 Hz, 1H), 7.47 (dd,J=8.6, 4.3 Hz, 1H), 7.13 (d, J=1.7 Hz, 1H), 6.85 (d, J=1.7 Hz, 1H), 4.57(s, 0H), 2.42 (s, 3H), 2.39 (s, 3H), 2.27 (s, 3H), 1.93 (dt, J=7.0, 3.4Hz, 1H). LCMS (m/z+1) 411.24.

Example 125, and Example 1266-(3,5-dimethylisoxazol-4-yl)-4-(6-(trifluoromethyl)quinolin-5-yl)-1H-benzo[d]imidazol-2(3H)-oneand6-(3,5-dimethylisoxazol-4-yl)-4-(6-(trifluoromethyl)quinolin-7-yl)-1H-benzo[d]imidazol-2(3H)-one

To a microwave vial containing6-(3,5-dimethylisoxazol-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2(3H)-one(100 mg, 0.28 mmol, 1 equiv.) was added5-chloro-6-trifluoromethyl)quinolone (140 mg, 0.56 mmol, 2 equiv.),Cs2CO3 (450 mg, 1.41 mmol, 5 equiv.) and PEPPSI™-IPr catalyst (45 mg,0.056 mmol, 0.2 equiv.) and dissolved in DME-H₂O (4 mL, 0.2 M, 2/1,v/v). The mixture was heated to 120° C. for 30 min in microwave. Thereaction was concentrated in vacuo and purification was carried out byreverse phase HPLC.

1H NMR (400 MHz, Methanol-d4) δ 9.00 (dd, J=4.2, 1.6 Hz, 1H), 8.32 (d,J=9.1 Hz, 1H), 8.19 (d, J=9.0 Hz, 1H), 7.97-7.76 (m, 1H), 7.56 (dd,J=8.6, 4.3 Hz, 1H), 7.16 (d, J=1.5 Hz, 1H), 6.91 (d, J=1.4 Hz, 1H), 2.42(s, 3H), 2.27 (s, 3H). LCMS (m/z+1) 425.38

1H NMR (400 MHz, Methanol-d4) δ 9.03 (ddd, J=20.6, 4.3, 1.6 Hz, 1H),8.69-8.48 (m, 1H), 8.32 (d, J=9.0 Hz, 0H), 8.19 (d, J=9.0 Hz, 0H), 8.09(s, 1H), 7.86 (d, J=8.7 Hz, 0H), 7.72 (dd, J=8.4, 4.4 Hz, 1H), 7.56 (dd,J=8.6, 4.3 Hz, 0H), 7.12 (dd, J=32.1, 1.5 Hz, 1H), 6.93 (d, J=10.3 Hz,1H), 2.42 (s, 3H), 2.27 (s, 3H). LCMS (m/z+1) 425.38.

Example 127 and Example 128(S)-6-(3,5-dimethylisoxazol-4-yl)-4-(6-(trifluoromethyl)quinolin-5-yl)-1H-benzo[d]imidazol-2(3H)-oneand(R)-6-(3,5-dimethylisoxazol-4-yl)-4-(6-(trifluoromethyl)quinolin-5-yl)-1H-benzo[d]imidazol-2(3H)-one

The crude was separated to provide the two atropisomers using HPLCchiral separation.

1H NMR (400 MHz, Methanol-d4) δ 9.00 (dd, J3=4.2, 1.6 Hz, 1H), 8.32 (d,J=9.1 Hz, 1H), 8.19 (d, J=9.0 Hz, 1H), 7.97-7.76 (m, 1H), 7.56 (dd,J=8.6, 4.3 Hz, 1H), 7.16 (d, J=1.5 Hz, 1H), 6.91 (c, J=1.4 Hz, 1H), 2.42(s, 3H), 2.27 (s, 3H). LCMS (m/z+1) 425.38.

Example 1295-(3,5-dimethylisoxazol-4-yl-1-methyl-7-(6-(trifluoromethyl)quinolin-5-yl)-1H-benzo[d]imidazol-2(3B)-one

To a microwave vial containing5-(3,5-dimethylisoxazol-4-yl)-1-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2(3H)-one(30 mg, 0.08 mmol, 1 equiv.) was added5-bromo-6-(trifluoromethyl)quinoline (68 mg, 0.24 mmol, 3 equiv.),Cs₂CO₃ (105 mg, 0.33 mmol, 4 equiv.) and PEPPSI™-IPr catalyst (11 mg,0.016 mmol, 0.2 equiv.) and dissolved in DME-H₂O (4 mL, 0.2 M, 2/1,v/v). The mixture was heated to 120° C. for 30 min in microwave. Thereaction was concentrated in vacuo and purification was then carried outby reverse phase HPLC.

1H NMR (400 MHz, Methanol-d4) δ 9.28 (s, 1H), 8.30-8.19 (m, 1H), 7.98(ddd, J=8.5, 6.9, 1.4 Hz, 1H), 7.70 (ddd, J=8.3, 6.9, 1.2 Hz, 1H),7.59-7.44 (m, 1H), 7.23 (d, J=1.6 Hz, 1H), 6.92 (d, J=1.5 Hz, 1H), 2.54(s, 4H), 2.41 (s, 3H), 2.25 (s, 4H). LCMS (m/z+1) 385.22

Example 1305-(3,5-dimethylisoxazol-4-yl)-1-methyl-7-(6-(trifluoromethoxy)quinolin-5-yl)-1H-benzo[d]imidazol-2(3H)-one

To a microwave vial containing5-(3,5-dimethylisoxazol-4-yl)-1-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2(3H)-one(52 mg, 0.14 mmol, 1 equiv.) was added5-bromo-6-(trifluoromethoxy)quinoline (124 mg, 0.42 mmol, 3 equiv.),Cs2CO3 (230 mg, 0.70 mmol, 5 equiv.) and PEPPSI™-IPr catalyst (9.5 mg,0.014 mmol, 0.1 equiv.) and dissolved in DME-H₂O (4 mL, 0.2 M, 2/1,v/v). The mixture was heated to 120° C. for 30 min in microwave. Thereaction was concentrated in vacuo and purification was then carried outby reverse phase HPLC.

1H NMR (400 MHz, Methanol-d4) δ 8.97 (dd, J=4.3, 1.6 Hz, 1H), 8.31 (d,J=9.4 Hz, 1H), 8.11-7.83 (m, 2H), 7.59 (dd, J=8.6, 4.3 Hz, 1H), 7.20 (d,J=1.6 Hz, 1H), 6.89 (s, 1H), 2.61 (s, 3H), 2.41 (s, 3H), 2.26 (s, 3H).9F NMR (376 MHz, Methanol-d₄) δ −58.53. LCMS (m/z+1) 455.29

Example 1314-(6-(3,5-dimethyloxazol-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-3-methylquinoline1-oxide

A solution of6-(3,5-dimethylisoxazol-4-yl)-4-(3-methylquinolin-4-yl)-1H-benzo[d]imidazol-2(3H)-one(30 mg, 0.08 mmol) and mCPBA (100 mg, 0.58 mmol) in dichloromethane (0.5mL) and methanol (0.5 mL) was stirred for 1 hour at room temperature.The reaction was quenched with sodium sulfite solution, extracted withethyl acetate and purified by reverse-phase HPLC.

C22H18N4O3. 387.1 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ 10.90 (d, J=1.9 Hz,1H), 10.48 (d, J=2.0 Hz, 1H), 8.73 (s, 1H), 8.62-8.56 (m, 1H), 7.81-7.75(m, 1H), 7.63 (ddd, J=8.3, 6.9, 1.3 Hz, 1H), 7.41 (dd, J=8.6, 1.3 Hz,1H), 7.10-7.02 (m, 1H), 6.88 (d, J=1.6 Hz, 1H), 2.43 (s, 3H), 2.25 (s,3H), 2.17 (s, 3H).

Example 132(R)-5-(6-(3,5-dimethylisoxazol-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-6-methylquinoline1-oxide

C₂₂H₁₈N₄O₃. 387.1 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ 10.86 (d, J=2.2 Hz,1H), 10.40 (s, 1H), 8.63-8.48 (m, 2H), 7.80 (d, J=9.0 Hz, 1H), 7.34 (dd,J=8.8, 6.0 Hz, 1H), 7.26-7.15 (m, 1H), 7.05-6.96 (m, 1H), 6.81 (t, J=1.2Hz, 1H), 2.40 (s, 3H), 2.24 (d, J=7.9 Hz, 6H).

Example 1336-(3,5-dimethylisoxazol-4-yl)-4-(hydroxydi(pyridin-2-yl)methyl)-1H-benzo[d]imidazol-2(3H)-one

Butyllithium (1.6M solution in hexanes, 24 mL, 38 mmol) was addeddropwise over 20 minutes to a solution of 2-bromopyridine (3.7 mL, 38mmol in methyl-THF (100 mL) at −78° C. The reaction mixture was stirredfor 1 hour and a solution of methyl2,3-diamino-5-(3,5-dimethylisoxazol-4-yl)benzoate (2.0 g, 7.7 mmol) in20 mL of methyl-THF was added. The reaction mixture was warmed to roomtemperature, stirred for 30 minutes and quenched with water. Thereaction mixture was extracted with ethyl acetate and purified by silicagel chromatography (90:9:1 ethyl acetate/methanol/ammonium hydroxide) togive(2,3-diamino-5-(3,5-dimethylisoxazol-4-yl)phenyl)di(pyridin-2-yl)methanolas an orange powder.

CDI (1.1 g, 6 mmol) was added to a solution of(2,3-diamino-5-(3,5-dimethylisoxazol-4-yl)phenyl)di(pyridin-2-yl)methanol(1.43 g, 3.7 mmol) in THF (10 mL) and the reaction mixture was stirredfor 3 days. The reaction mixture was diluted with 100 mL water and 100mL ethyl acetate and sonicated and filtered to yield the desiredproduct.

C23H19N5O3. 414.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 10.69 (d, J=1.6 Hz,1H), 9.79 (s, 1H), 8.49 (ddd, J=4.9, 1.8, 0.9 Hz, 2H), 7.80 (td, J=7.7,1.8 Hz, 2H), 7.58 (dt, J=8.0, 1.1 Hz, 2H), 7.30 (ddd, J=7.5, 4.8, 1.1Hz, 2H), 6.86 (s, 1H), 6.81 (d, J=1.5 Hz, 1H), 6.56 (d, J=1.6 Hz, 1H),2.26 (s, 3H), 2.06 (s, 3H).

The following compound was made similarly to6-(3,5-dimethylisoxazol-4-yl)-4(hydroxydi(pyridin-2-yl)methyl)-1H-benzo[d]imidazol-2(3H)-one using2-pyridyl-6-magniesiumbromide:

Example 1346-(3,5-dimethylisoxazol-4-yl)-4-hydroxybis(6-methylpyridin-2-yl)methyl)-1H-benzo[d]imidazol-2(3H)-one

GS-694472 C₂₅H₂₃N₅O₃. 442.1 (M+1). 1H NMR (400 MHz, DMSO-d₆) δ 10.77 (s,1H), 10.07 (s, 1H), 7.89 (di, J=17.5 Hz, 2H), 7.51 (t, J=8.0 Hz, 2H),7.39 (di, J=37.6 Hz, 2H), 6.86 (di, J=1.3 Hz, 1), 2.50 (s, 6H), 2.27 (s,3H), 2.08 (s, 3H).

Example 1356-(3,5-dimethylisoxazol-4-yl)-4-(1-hydroxy-2-methyl-1-(pyridin-2-yl)butyl)-1H-benzo[d]imidazol-2(3H)-oneStep 1

Methyl ester (25 g, 0.096 mol) was dissolved in a mixture of MeOH (400mL) and 1 M NaOH (200 mL), an air condenser was attached and thereaction was heated to 60° C. for 1.5 hours. Reaction was allowed tocool to room temperature and concentrated in vacuo. The residue was thendiluted in a minimal amount of water and neutralized with 1 M HCl untilpH 6-7. The precipitate was collected by vacuum filtration, taken up inMeOH, and concentrated in vacuo to give2,3-diamino-5-(3,5-dimethylisoxazol-4-yl)benzoic acid as a brown powder.Material was used without further purification.

C12H13N3O3 248.1 (M+1)

2,3-diamino-5-(3,5-dimethylisoxazol-4-yl)benzoic acid (22 g, 0.089 mol)was dissolved in DMF (C=3.0 M) and HATU (1.3 eq), DIPEA (7 eq), andN,O-dimethylhydroxylamine hydrochloride (2.5 eq) were added in oneportion and the reaction was allowed to stir under air at roomtemperature for 1 hr. The reaction was concentrated in vacuo and theresidue was dissolved in ethyl acetate. The solution was washed oncewith NaHCO₃ and three times with brine. The crude was concentrated invacuo and purified via silica gel chromatography to give2,3-diamino-5-(3,5-dimethylisoxazol-4-yl)-N-methoxy-N-methylbenzamide asa light brown powder.

2,3-diamino-5-(3,5-dimethylisoxazol-4-yl)-N-methoxy-N-methylbenzamide(25 g, 0.086 mol) was dissolved in a 1:1 mixture (32 mL total) oftetraethylorthocarbonate and AcOH and allowed to stir under air at roomtemperature for 1.5 hr. The reaction mixture was concentrated in vacuoat room temperature and the crude residue was dissolved in EtOAc. Thesolution was washed three times with bicarb, once with water, andorganic layer was concentrated in vacuo to give6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-N-methoxy-N-methyl-1H-benzo[d]imidazole-4-carboxamideas a dark oil. Crude material was used without further purification.

6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-N-methoxy-N-methyl-1H-benzo[d]imidazole-4-carboxamide(23 g, 0.067 mol) was dissolved in THF (80 mL, 1.0 M) and Boc₂O (2 eq),DMAP (0.4 eq), and triethylamine (3.5 eq) were added to the reactionmixture and allowed to stir under air at room temperature for 1 hr.Reaction mixture was then concentrated in vacuo and purified by silicagel chromatography (80-100% EtOAc/hex) to give tert-butyl6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-4-(methoxy(methyl)carbamoyl)-1H-benzo[d]imidazole-1-carboxylate%) as a white powder.

2-bromopyridine (4.5 mmol, 2 eq) was dissolved in 2-MeTHF (C=0.15 M) andcooled to −78° C. under Ar. n-BuLi (1.6 M, 2 eq) was added dropwise tothe solution over 15 minutes and the reaction was allowed to stir at−78° C. for 1 hour. tert-butyl6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-4-(methoxy(methyl)carbamoyl)-1H-benzo[d]imidazole-1-carboxylate(1 g, 2.25 mmol) was dissolved in a minimal amount of 2-MeTHF and addedto the reaction via syringe in one portion and the reaction was thenallowed to slowly warm to room temperature. The reaction was quenchedwith water, diluted with EtOAc, washed twice with brine, andconcentrated in vacuo. The crude material was purified by silica gelchromatography to give tert-butyl6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-4-picolinoyl-1H-benzo[d]imidazole-1-carboxylate(300 mg, 29%) as a yellow powder and(6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazol-4-yl)(pyridin-2-yl)methanone(460 mg, 56%) as a pale yellow powder.

(6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazol-4-yl)(pyridin-2-yl)methanone(20 mg, 0.055 mmol) was dissolved in dry THF (0.55 mL) under argon.Sec-butylmagnesium bromide (1.0 M in THF, 0.27 mL, 0.28 mmol) was addeddropwise and the reaction was allowed to stir for 10 minutes. Thereaction was quenched with water, concentrated and purified byreverse-phase HPLC to give1-(6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazol-4-yl)-2-methyl-1-(pyridin-2-yl)butan-1-olintermediate. Intermediate was taken up in 0.5 mL EtOH and 0.3 mL 4.0MHCl/dioxane and heated to 65° C. for 1 hr. Reaction was concentrated andpurified by reverse phase HPLC to afford the desired product

CH₂₄H₂₄N₄O₃ 393.5 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ 10.64 (s, 1H), 9.99(s, 1H), 8.54 (s, 1H), 7.84 (s, 2H), 7.27 (s, 1H), 7.11 (t, J=1.8 Hz,1H), 6.71 (d, J=3.1 Hz, 1H), 2.36 (d, J=5.7 Hz, 3H), 2.18 (d, J=5.8 Hz,3H), 0.87 (t, J=7.3 Hz, 5H), 0.80 (d, J=7.2 Hz, 3H), 0.62 (d, J=6.5 Hz,2H).

Example 1364-(cyclopropyl(hydroxy)(pyridin-2-yl)methyl)-6-(3,5-dimethyloxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one

(6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazol-4-yl)(pyridin-2-yl)methanone(40 mg, 0.11 mmol) was dissolved in dry THF (1.1 mL) andcyclopropylmagnesium bromide (0.5 M in diethylether, 1.1 mL, 0.55 mmol)was added dropwise at rt and the reaction was allowed to stir for 10minutes. The reaction was quenched with water, concentrated, andpurified by reverse-phase HPLC to givecyclopropyl(6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazol-4-yl)(pyridin-2-yl)methanolintermediate which was taken up in 1.0 mL EtOH and 0.7 mL 4.0MHCl/dioxane and heated for 2 hours at 65° C. Reaction was thenconcentrated down and purified by reverse-phase HPLC to afford thedesired product as a white powder.

C21H20N4O3 377.3 (M+1)

1H NMR (400 MHz, DMSO-d6) δ 10.66 (s, 1H), 9.73 (s, 1H), 8.54 (s, 1H),7.92 (s, 1H), 7.71 (d, J=8.0 Hz, 1H), 7.40 (s, 1H), 7.27 (s, 1H), 6.81(s, 1H), 2.39 (s, 3H), 2.21 (s, 3H), 2.01 (s, 1H), 0.54 (d, J=5.6 Hz,3H), 0.29 (d, J=10.3 Hz, 1H).

Example 1376-(3,5-dimethylisoxazol-4-yl)-4-(1-hydroxy-1-(pyridin-2-yl)propyl)-1H-benzo[d]imidazol-2(3H-one

(6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazol-4-yl)(pyridin-2-yl)methanone(20 mg. 0.055 mmol) was dissolved in dry THF (0.5 mL) and ethylmagnesiumbromide (1.0 M, 0.27 mL, 0.27 mmol) was added dropwise. The reaction wasallowed to stir at r.t. for 10 minutes and then a mixture of EtOH (1 mL)and 4.0M HCl/dioxane (0.5 mL) was added and the reaction was heated to65° C. for 3 hours. The reaction was concentrated and purified byreverse-phase HPLC to afford the desired product as a white powder.

C20H20N4O3 365.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 10.67 (s, 1H), 9.89(s, 1H), 8.57 (s, 1H), 7.88 (s, 2H), 7.35 (s, 1H), 6.97 (s, 1H), 6.75(s, 1H), 2.42 (d, J=9.1 Hz, 2H), 2.35 (s, 3H), 2.17 (s, 3H), 0.79 (t,J=7.2 Hz, 3H).

Example 1384-(cyclopentyl(hydroxy)(pyridin-2-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one

(6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazol-4-yl)(pyridin-2-yl)methanone(50 mg, 0.14 mmol) was dissolved in dry THF (1.4 mL) under argon andcooled to 0° C. Cyclopentylmagnesium chloride (2.0 M, 0.14 mL, 0.28mmol) was added dropwise and reaction was allowed to stir for 10 minutesthen quenched with water. Reaction mixture was extracted three timeswith EtOAc and combined organic layers were washed once with water andconcentrated. Residue was taken up in EtOH (1.5 mL) and 4.0M HCl/dioxane(0.75 mL) and heated to 65° C. for 2 hours. Reaction was concentratedand purified by reverse-phase HPLC to afford the desired product as awhite powder.

C23H24N4O3. 405.2 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 10.77 (d, J=5.3 Hz,1H), 10.03 (s, 1H), 8.67 (s, 1H), 8.14 (s, 1H), 7.94 (s, 1H), 7.61 (s,1H), 7.19 (s, 1H), 6.80 (s, 1H), 3.55-3.45 (m, 1H), 2.39 (s, 3H), 2.22(s, 3H), 1.69-1.60 (m, 2H), 1.55 (dd, J=11.5, 5.4 Hz, 3H), 1.46 (d,J=7.7 Hz, 1H), 1.31 (d, J=11.1 Hz, 1H), 1.12 (s, 1H).

Example 1396-(3,5-dimethylisoxazol-4-yl)-4-(1-hydroxy-1-(pyridin-2-yl)pent-4-en-1-yl)-H-benzo[d]imidazol-2(3H)-one

Magnesium metal (20 mg, 0.82 mmol) was taken up in THF (1.5 mL) and(bromomethyl)cyclopropane (100 mg, 0.71 mmol) was added dropwise and thereaction was heated to 65° C. for 1 hr. (Cyclopropylmethyl)magnesiumbromide (0.5 M, 0.83 mL, 0.41 mmol) was then added dropwise to asolution of(6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazol-4-yl)(pyridin-2-yl)methanone(50 mg, 0.14 mmol) in dry THF (1.4 mL) which was cooled to 0° C.Reaction mixture was allowed to stir for 10 mins, quenched with waterand extracted three times with EtOAc. Combined organic layers werewashed once with water and concentrated. Residue was dissolved in amixture of EtOH (1.5 mL) and 4.0M HCl/dioxane (0.75 mL) and heated for 2hours at 65° C. Reaction was then concentrated and purified byreverse-phase HPLC to to afford the desired product as a white powder.

C22H22N4O3. 391.5 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 10.68 (s, 1H), 9.93(s, 1H), 8.55 (s, 1H), 7.88 (s, 2H), 7.32 (s, 1H), 6.95 (s, 1H), 6.75(s, 1H), 5.82 (dd, J=9.8, 7.0 Hz, 1H), 5.00-4.85 (m, 3H), 2.35 (s, 3H),2.16 (s, 3H), 2.10-1.90 (m, 4H).

Example 1406-(3,5-dimethylisoxazol-4-yl)-4-(4,4,4-trifluoro-1-hydroxy-1-(pyridin-2-yl)butyl)-1H-benzo[d]imidazol-2(3H)-one

(6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazol-4-yl)(pyridin2-yl)methanone (50 mg, 0.14 mmol) was dissolved in dry THF (1.4 mL) andcooled to 0° C. (3,3,3-trifluoropropyl)magnesium bromide (0.5 M. 0.55mL, 0.28 mmol) was added dropwise and the reaction was allowed to stirfor 10 mins and then quenched with water. Reaction was extracted threetimes with EtOAc and combined organic layers were washed once with waterand concentrated. Residue was taken up in EtOH (1.5 mL) and 4.0MHCl/dioxane (0.75 mL), heated to 65° C. for two hours, concentrated,then purified by reverse-phase HPLC to afford the desired product as awhite powder.

C21H19F3N4O3 433.4 (M+1). ¹H NMR (400 MHz, DMSO-d6) δ 10.72 (s, 1H),10.05 (s, 1H), 8.56 (d, J=4.6 Hz, 1H), 7.88 (s, 2H), 7.31 (s, 1H), 6.82(s, 1H), 6.76 (s, 1H), 2.67 (s, 1H), 2.60 (d, J=4.0 Hz, 1H). 2.32 (s,4H), 2.16 (s, 2H), 2.13 (s, 3H).

Example 1416-(3,5-dimethylisoxazol-4-yl)-4-(1-hydroxy-2-methyl-1-(pyridin-2-yl)propyl)-1H-benzo[d]imidazol-2(3H)-one

(6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazol-4-yl)(pyridin-2-yl)methanone(50 mg, 0.14 mmol) was dissolved in dry THF (1.4 mL) and cooled to 0 OC.Isopropylmagnesium bromide (2.0 M, 0.14 mL, 0.28 mmol) was addeddropwise and the reaction was allowed to stir for 10 mins and thenquenched with water. Reaction was extracted three times with EtOAc andcombined organic layers were washed once with water and concentrated.Residue was taken up in EtOH (1.5 mL) and 4.0M HCl/dioxane (0.75 mL),heated to 65° C. for two hours, concentrated, then purified byreverse-phase HPLC to afford the desired product as a white powder.

C21H22N4O3 379.3 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 10.70 (s, 1H), 10.01(d, J=2.1 Hz, 1H), 8.60 (s, 1H), 7.91 (s, 2H), 7.41 (s, 1H), 7.15 (s,1K), 6.74 (s, 1H), 3.17 (s, 1H), 2.37 (s, 3H), 2.33 (d, J=1.7 Hz, 0H),2.20 (s, 3H), 2.15 (s, 0H), 1.23 (d, J=6.7 Hz, 1H), 0.93 (d, J=6.0 Hz,3H), 0.65 (d, J=6.9 Hz, 3H).

Example 1424-(cyclobutyl(hydroxy)(pyridin-2-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one

(6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazol-4-yl)(pyridin-2-yl)methanone(50 mg, 0.14 mmol) was dissolved in dry THF (1.4 mL) and cooled to 0° C.Cylobutylmagnesium chloride (0.5 M, 1.1 mL, 0.55 mmol) was addeddropwise and the reaction was allowed to stir for 10 mins and thenquenched with water. Reaction was extracted three times with EtOAc andcombined organic layers were washed once with water, concentrated, andpurified by reverse-phase HPLC to givecyclobutyl(6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazol-4-yl)(pyridin-2-yl)methanolintermediate. The intermediate was taken up in EtOH (1.5 mL) and 4.0 MHCl/dioxane and heated to 65° C. for 2 hours, concentrated and purifiedby reverse-phase HPLC to afford the desired product as a white powder.

C22H22N4O3 391.5 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 10.70 (s, 1H), 9.93(d, J=2.6 Hz, 1H), 8.58 (s, 1H), 7.96 (s, 1H), 7.72 (d, J=8.0 Hz, 1H),7.43 (s, 1H), 7.00 (s, 1H), 6.79 (d, J=2.1 Hz, 1H), 3.82-3.71 (m, 1H),2.39 (s, 3H), 2.21 (s, 3H), 2.19-2.10 (m, 1H), 2.02-1.94 (m, 1H), 1.91(s, 1H), 1.80 (q, J=9.1 Hz, 1H), 1.67 (t, J=9.7 Hz, 1H), 1.44 (q, J=6.2,3.9 Hz, 1H).

Example 1436-(3,5-dimethylisoxazol-4-yl)-4-(1-hydroxy-3,3-dimethyl-1-(pyridin-2-yl)butyl)-1H-benzo[d]imidazol-2(3H)-one

(6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazol-4-yl)(pyridin-2-yl)methanone(50 mg, 0.14 mmol) was dissolved in dry THF (1.4 mL) and cooled to 0° C.Neopentylmagnesium chloride (1.0 M, 0.55 mL, 0.55 mmol) was addeddropwise and the reaction was allowed to stir for 10 mins and thenquenched with water. Reaction was extracted three times with EtOAc andcombined organic layers were washed once with water, concentrated, andpurified by reverse-phase HPLC to give1-(6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazol-4-yl)-3,3-dimethyl-1-(pyridin-2-yl)butan-1-olintermediate. The intermediate was taken up in EtOH (1.5 mL) and 4.0 MHCl/dioxane and heated to 65° C. for 2 hours, concentrated and purifiedby reverse-phase HPLC to afford the desired product as a white powder.

C23H26N4O3 407.3 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 10.70 (d, J=4.6 Hz,1H), 9.94 (d, J=2.5 Hz, 1H), 8.58 (s, 1H), 7.98 (s, 2H), 7.38 (s, 1H),7.09 (d, J=2.5 Hz, 1H), 6.73 (d, J=2.9 Hz, 1H), 2.51 (s. 2H), 2.35 (s,3H), 2.17 (d, J=1.0 Hz, 3H), 0.79 (s, 9H).

Example 1444-(cyclohexyl(hydroxy)(pyridin-2-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one

(6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazol-4-yl)(pyridin-2-yl)methanone(50 mg, 0.14 mmol) was dissolved in dry THF (1.4 mL) and cooled to 0 OC.Cyclohexylmagnesium chloride (2.0 M, 0.21 mL, 0.41 mmol) was addeddropwise and the reaction was allowed to stir for 10 mins and thenquenched with water. Reaction was extracted three times with EtOAc andcombined organic layers were washed once with water, concentrated, andpurified by reverse-phase HPLC to givecyclohexyl(6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazol-4-yl)(pyridin-2-yl)methanolintermediate. The intermediate was taken up in EtOH (1.5 mL) and 0.2 mLconcentrated HCl and heated to 65° C. for 2 hours and concentratedafford the desired product as a white powder.

C24H26N4O3 419.8 (M+1). 1H NMR (400 MHz, Methanol-d4) δ 8.77 (d, J=5.7Hz, 1H), 8.54 (t, J=7.5 Hz, 1H), 8.15 (d, J=7.9 Hz, 1H), 7.97 (dd,J=7.3, 5.7 Hz, 1H), 7.24 (d, J=1.4 Hz, 1H), 6.99 (d, J=1.2 Hz, 1H), 2.84(d, J=10.6 Hz, 1H), 2.42 (s, 3H), 2.27 (s, 3H), 2.00-1.72 (m, 5H),1.55-1.33 (m, 5H).

Example 1454-((6-chloropyridin-2-yl)(hydroxy)(pyridin-2-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one

To a solution of 2-bromo-6-chloropyridine (83 mg, 0.43 mmol) in 2-MeTHF(1.5 mL) cooled to −78° C. was added n-BuLi (1.6 M, 0.27 mL, 0.43 mmol)dropwise and the reaction was allowed to stir for 40 mins. A solution of(6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazol-4-yl)(pyridin-2-yl)methanone(100 mg, 0.22 mmol) in 2-MeTHF (0.5 mL) was added to the reaction andthe reaction was allowed to stir for an additional 10 mins at −78° C.and then quenched with water. The reaction mixture was extracted threetimes with EtOAc and combined organic layers were washed once withwater, concentrated, and purified by silica gel chromatography to yield(6-chloropyridin-2-yl)(6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazol-4-yl)(pyridin-2-yl)methanol(51 mg, 41%) as a white solid. The solid (26.5 mg, 0.055 mmol) was takenup in EtOH (1 mL) and 4M HCl/dioxane (0.5 mL) and heated for two hoursat 65° C. and then concentrated to afford the desired product as a paleyellow powder.

C23H18ClN5O3 448.9 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 10.80-10.72 (m,1H), 9.87 (s, 1H), 8.54 (d, J=4.8 Hz, 1H), 7.89 (t, J=7.9 Hz, 2H), 7.63(d, J=8.1 Hz, 1H), 7.56 (d, J=7.7 Hz, 1H), 7.45 (d, J=7.9 Hz, 1H), 7.39(s, 1H), 6.86 (s, 1H), 6.51 (s, 1H), 2.30 (s, 3H), 2.10 (s, 3H).

Example 1466-(3,5-dimethylisoxazol-4-yl)-4-(hydroxy(6-(2-methoxyethoxy)pyridin-2-yl)(pyridin-2-yl)methyl)-1H-benzo[d]imidazol-2(3H)-one

2-methoxyethanol (25 mg, 0.33 mmol) was dissolved in THF (0.5 mL) andcooled to 0° C. Sodium hydride (8 mg, 0.33 mmol) was added in oneportion and the reaction was allowed to come to rt and stir for 10minutes. The reaction was then cooled back to 0° C. and tert-butyl4-((6-chloropyridin-2-yl)(hydroxy)(pyridin-2-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazole-1-carboxylate(24 mg, 0.04 mmol) was added and the reaction was sealed and heated to80° C. overnight. Reaction was concentrated and the residue was taken upin EtOH (1.5 mL) and 4M HCl/dioxane (0.5 mL) and heated for 2 hours at60° C. The reaction was cooled to rt and filtered to remove the sodiumsalt Filterate was concentrated to afford the desired product as a brownfilm.

C26H25N5O5 488.5 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 10.81 (s, 1H), 9.97(s, 1H), 8.63 (s, 1H), 7.77 (d, J=7.9 Hz, 1H), 7.69 (s, 1H), 7.28 (s,1H), 6.89 (s, 1H), 6.81-6.72 (m, 1H), 6.41 (s, 1H), 4.10 (d, J=4.5 Hz,2H), 3.75-3.61 (m, 2H), 3.15 (s, 3H), 2.26 (s, 3H), 2.06 (s, 3H).

Example 1476-(3,5-dimethylisoxazol-4-yl)-4-(hydroxy(6-methylpyridin-2-yl)(pyridin-2-yl)methyl)-1H-benzo[d]imidazol-2(3H)-one

In a 2-neck, 50-mL round-bottom flask, a solution of 6-bromo-2-picoline(28.6 mg, 0.177 mmol) in 2 mL of 2-methyltetrahydrofuran was cooled to−78° C. in a dry ice/acetone bath while stirring under nitrogen. To thisstirring solution, a 1.42 M n-butyllithium solution in hexanes (0.12 mL,0.17 mmol) was added dropwise and the reaction mixture was stirred at−78° C. for 30 minutes. Tert-butyl6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-4-picolinoyl-1H-benzo[d]imidazole-1-carboxylate(34.8 mg, 0.0752 mmol) was added dropwise in a solution of 1 mL of2-methyltetrahydrofuran. The reaction mixture was warmed to roomtemperature for 30 minutes before the reaction was quenched with brineand diluted with ethyl acetate. The organic layer was separated andsaved and the aqueous layer was extracted three times with ethylacetate. The organic layers were dried over sodium sulfate, decanted andconcentrated. C31H33N5O5. 556.1 (M+1).

The crude intermediate was taken up in 2 mL of ethanol and transferredto a microwave vial. 4M hydrochloric acid in dioxane (0.10 mL, 0.40mmol) was added to the reaction mixture and the vial was sealed andheated at 70° C. for 1 hour or until reaction completion. The reactionmixture was concentrated and the product was isolated by preparatoryHPLC as a yellow oil

C24H21N5O3. 428.0 (M+1). 1H NMR (400 MHz, Methanol-d4) δ 8.68 (ddd,J=5.3, 1.8, 0.9 Hz, 1H), 8.25-8.16 (m, 2H), 7.92 (dt, J=8.1, 1.0 Hz,1H), 7.73-7.61 (m, 3H), 7.09 (d, J=1.5 Hz, 1H), 6.42 (d, J=1.5 Hz, 1H),2.75 (s, 3H), 2.31 (s, 3H), 2.14 (s, 3H).

Example 1486-(3,5-dimethylisoxazol-4-yl)-4-((6-ethylpyridin-2-yl)(hydroxy)(pyridin-2-yl)methyl)-1H-benzo[d]imidazol-2(3H)-one

A procedure similar to that used for Example 162 was used to produce theintermediate (C3H₃N₅O₅. 570.1 (M+1)), which was taken directly to thedeprotection step to yield a yellow oil.

C₂₅H23N₅O₃. 442.0 (M+1). ¹H NMR (400 MHz, Methanol-d₄) δ 8.75-8.68 (m,1H), 8.29 (td, J=7.9, 1.7 Hz, 1H), 8.18 (t, J=7.9 Hz, 1H), 7.94 (dt,J=8.1, 1.0 Hz, 1H), 7.76 (ddd, J=7.7, 5.4, 1.1 Hz, 1H), 7.70-7.62 (m,2H), 7.09 (d, J=1.5 Hz, 1H), 6.43 (d, J=1.5 Hz, 1H), 3.00 (q, J=7.6 Hz,2H), 2.31 (s, 3H), 2.13 (s, 3H), 1.32 (t, J=7.6 Hz, 3H).

Example 1496-(3,5-dimethylisoxazol-4-yl)-4-(hydroxy(phenyl)(pyridin-2-yl)methyl)-Hbenzo[d]imidazol-2(3H)-one

In a 2-neck, 50-mL round bottom flask, a solution of(6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazole-4-yl)(pyridin-2-yl)methanone(31.5 mg, 0.0870 mmol) in 2 mL of tetrahydrofuran was cooled to 0° C.while stirring under nitrogen. A 2M solution of phenylmagnesium chloridein tetrahydrofuran (0.13 mL, 0.26 mmol) was added dropwise to thereaction mixture and allowed to warm to room temperature for 30 minutes.The reaction mixture was quenched with 2 M aqueous hydrochloric acid andneutralized with aqueous sodium bicarbonate. The aqueous layer wasextracted with ethyl acetate three times, and the combined organiclayers were concentrated and taken directly to the deprotection step.C₂₆H₂₄N₄O₃, 441.1 (M+1).

The crude intermediate was dissolved in 3 mL of ethanol and transferredto a microwave vial. Hydrochloric acid in dioxane (0.10 mL, 0.40 mmol)was added and the reaction vial was sealed and heated at 70° C. for 1hour. The reaction mixture was concentrated down and the product wasisolated by preparatory HPLC as a white solid.

C26H24N4O3. 413.1 (M+1). 1H NMR (400 MHz, Methanol-d4) δ 8.80 (ddd,J=5.6, 1.7, 0.8 Hz, 1H), 8.38 (td, J=7.9, 1.7 Hz, 1H), 7.89 (ddd, J=7.8,5.6, 1.2 Hz, 1H), 7.77 (dt, J=8.1, 1.0 Hz, 1H), 7.51-7.41 (m, 3H), 7.37(dd, J=7.9, 1.8 Hz, 2H), 7.08 (d, J=1.5 Hz, 1H), 6.48 (d, J=1.5 Hz, 1H),2.30 (s, 3H), 2.13 (s, 3H).

Example 1506-(3,5-dimethylisoxazol-4-yl)-4-((3-ethylphenyl)(hydroxy)(pyridin-2-yl)methyl)-1-benzo[d]imidazol-2(3H)-one

In a 2-neck, 50-mL round bottom flask, l-bromo-3-ethylbenzene (43.2 mg,0.233 mmol) was cooled to −78° C. in 2 mL of tetrahydrofuran whilestirring under nitrogen. A 1.47 M solution of tert-butyllithium inpentane (310 μL, 0.456 mmol) was added dropwise and the reaction wasallowed to stir for 15 minutes. In a solution of 1 mL oftetrahydrofuran, tert-butyl6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-4-picolinoyl-1H-benzo[d]imidazole-1-carboxylate(35.0 mg, 0.0757 mmol) was added dropwise. The reaction mixture waswarmed to room temperature while stirring under nitrogen for 15 minutesor until reaction completion. The reaction mixture was slowly quenchedwith brine and diluted with ethyl acetate. The organic layer wasseparated and saved and the aqueous layer was extracted with ethylacetate three times. The organic layers were combined, dried over sodiumsulfate, decanted and concentrated.

The crude intermediate was dissolved in 1 mL of ethanol and transferredto a microwave vial before 4M hydrochloric acid in dioxane (0.100 mL,0.400 mmol) was added. The vial was sealed and heated at 70° C. for onehour or until reaction completion. The reaction mixture was concentratedand isolated by preparatory HPLC to yield the title compound.

C26H24N4O3. 441.1 (M+1). 1H NMR (400 MHz, Methanol-d4) δ 8.89-8.81 (m,1H), 8.58 (td, J=8.0, 1.6 Hz, 1H), 8.08 (ddd, J=7.4, 5.8, 1.2 Hz, 1H),7.92-7.83 (m, 1H), 7.40 (t, J=7.7 Hz, 1H), 7.36-7.29 (m, 2H), 7.14 (d,J=1.7 Hz, 1H), 7.11 (d, J=1.5 Hz, 1H), 6.47 (d, J=1.5 Hz, 1H), 2.69 (q,J=7.6 Hz, 2H), 2.31 (s, 3H), 2.13 (s, 3H), 1.23 (t, J=7.6 Hz, 3H).

Example 1516-(3,5-dimethylisoxazol-4-yl)-4-(hydroxy(pyridin-2-yl)(m-tolyl)methyl)-1H-benzo[d]imidazol-2(3H)-one

A procedure similar to that used for Example 165 was used to produce theintermediate (C₂₇H₂₆N₄O₃, 455.1 (M+1)) which was immediately takenforward to the deprotection step to yield a yellow solid (7.7 mg, 23%).

C2H₂₂N₄O₃. 427.1 (M+1). ¹H NMR (400 MHz, Methanol-d₄) δ 8.87 (dd, J=6.0,1.4 Hz, 1H), 8.61 (td, J=7.9, 1.5 Hz, 1H), 8.16-8.06 (m, 1H), 7.90 (d,J=8.1 Hz, 1H), 7.39 (t, J=7.7 Hz, 1H), 7.34-7.25 (m, 2H), 7.14 (d, J=7.8Hz, 1H), 7.12 (d, J=1.5 Hz, 1H), 6.48 (d, J=1.5 Hz, 1H), 2.38 (s, 3H),2.32 (s, 3H), 2.14 (s, 3H).

Example 1526-(3,5-dimethylisoxazol-1-yl)-4-(hydroxy(3-methoxyphenyl)(pyridin-2-yl)methyl)-1H-benzo[d]imidazol-2(3H)-one

A procedure similar to that used to synthesize the compound of Example166 was used to produce the product as a white solid.

C₂₅H₂₂N₄O₄. 443.0 (M+1). ¹H NMR (400 MHz, Chloroform-d) δ 8.67 (m, 1H),8.56 (bs, 1H), 8.43 (bs, 1H), 7.72 (t, 2H), 7.34 (m, 1H), 7.10 (d, J=7.8Hz, 1H), 6.86 (m, 3H), 6.78 (d, J=7.8 Hz, 1H), 6.25 (s, 1H), 3.75 (s,3H), 2.25 (s, 3H), 2.10 (s, 3H).

Example 153 Preparation of6-(3,5-dimethylisoxazol-4-yl)-4-((7-fluoroquinolin-2-yl)(hydroxy)(phenyl)methyl)-1H-benzo[d]imidazol-2(3H)-one

Tert-butyl6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-4-(methoxy(methyl)carbamoyl)-1H-benzo[d]imidazole-1-carboxylatewas dissolved in THF (3 mL). To the solution was added a solution ofphenyl magnesium chloride (2M in THF, 0.508 mmol, 0.254 mmol) at −78° C.after the addition, the reaction was allowed to warm up to roomtemperature. The reaction was stirred for 17 hat the same temperature.The reaction mixture was quenched with water (30 mL). The whole wasextracted with AcOEt (30 mL×3). Organic layer was washed with brine (30mL) and dried over Na₂SO₄. The solvent was removed under a reducedpressure to give the crude product. The crude product was purified by asilica gel column chromatography (hexane: EtOAc, 7:1 to 3:1) to givetert-butyl4-benzoyl-6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazole-1-carboxylate.

C₂₆H₂₇N₃O₅. MS. m/z 462.2 (M+1).

To a solution of 7-fluoro-2-bromoquinoline (54.1 mg) in THF (2 mL) wasadded BuLi (1.6 M, 0.25 mL) at −78° C. After 5 min, a solution of phenylketone (60.0 mg) in THF (1 mL) was added at −78° C. The reaction wasimmediately allowed to warm up to room temperature and stirred for 30min. The reaction mixture was quenched with water (30 mL). The whole wasextracted with AcOEt (30 mL×3). Organic layer was washed with brine (30mL) and dried over Na₂SO₄. The solvent was removed under a reducedpressure to give the crude product. The crude product was treated withTFA to cleave the Boc group. The crude product was purified by a silicagel column chromatography (hexane: EtOAc, 7:1 to 3:1) to give tert-butyl4-benzoyl-6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazole-1-carboxylate(18.0 mg). tert-butyl4-benzoyl-6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazole-1-carboxylate.C₂₆H₂₇N₃O₅. MS. m/z 509.2 (M+1).

Tert-butyl4-benzoyl-6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazole-1-carboxylate(18.0 mg) was dissolved into EtOH (2 mL) and 4M HCl/dioxane (2 mL). Thesolution was heated at 70° C. for 30 min. The reaction mixture wasquenched with water (30 mL). The whole was extracted with EtOAc (30mL×3). Combined organic layers were washed with brine (50 mL). Thesolvent was removed under a reduced pressure to give a crude product.The crude product was purified by a a silica gel column chromatography(hexane: EtOAc, 7:1 to 3:1) to give tert-butyl4-benzoyl-6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazole-1-carboxylate.

C28H21FN4O3. MS. m/z 481.1 (M+1). 1H NMR (400 MHz, Methanol-d4) δ 8.31(1, J=8.7 Hz, 1H), 8.13 (dd, J=9.2, 5.3 Hz, 1H), 7.67-7.56 (m, 3H),7.40-7.25 (m, 5H), 6.98 (d, J=1.6 Hz, 1H), 6.61 (d, J=1.6 Hz, 1H), 2.28(s, 3H), 2.11 (s, 3H).

Example 1546-(3,5-dimethylisoxazol-4yl)-4-(hydroxy(phenyl)(quinolin-2-yl)methyl)-1H-benzo[d]imidazol-2(3H)-one

(6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazol-4-yl)(phenyl)(quinolin-2-yl)methanolwas synthesized in the similar fashion with tert-butyl4-benzoyl-6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazole-1-carboxylate.

C30H26N4O3. MS. m/z 491.2 (M+1).

C₂₈H₂₂N₄O₃. MS. m/z 463.1 (M+1).). ¹H NMR (400 MHz, Methanol-d₄) δ 8.30(d, J=8.6 Hz, 1H), 8.09 (di, J=8.6 Hz, 1H), 7.93 (d, J=8.6 Hz, 1H), 7.77(ddd, J=8.6, 7.0, 1.2 Hz, 1H), 7.61 (ddd, J=8.6, 7.0, 1.2 Hz, 1H), 7.54(d, J=8.6 Hz, 1H), 7.40-7.26 (m, 5H), 6.98 (d, J=1.5 Hz, 1H), 6.61 (d,J=1.5 Hz, 11H), 2.27 (s, 3H), 2.10 (s, 3H).

Example 155 6-(3,5-dimethylisoxazol-4-yl)4-(hydroxy(pyridin-2-yl)(quinolin-2-yl)methy)-1H-benzo[d]imidazol-2(3B)-one

(6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazol-4-yl)(pyridin-2-yl)(quinolin-2-yl)methanolwas synthesized in the similar fashion with tert-butyl4-benzoyl-6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazole-1-carboxylate.

C₂H₂₅N₅O₃. MS. m/z 492.2 (M+1).

C₂₈H₂₂N₄O₃. MS. m/z 463.1 (M+1).). ¹H NMR (400 MHz, Methanol-d₄) δ 8.78(dd, J=6.6, 1.0 Hz, 1H), 8.66 (d, J=8.8 Hz, 1H), 8.47 (td, J=8.8, 1.0Hz, 1H), 8.15-8.03 (m, 3H), 8.00-7.83 (m, 3H), 7.76 (t, J=8.0 Hz, 1H),7.07 (d, J=1.0 Hz, 1H), 6.46 (d, J=1.0 Hz, 1H), 2.22 (s, 3H), 2.04 (s,3H).

Example 156 1-tert-butyl 4-methyl6-(3,5-dimethylisoxazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1,4-dicarboxylate

Methyl 2-fluoro-3-nitrobenzoate (25 g, 0.126 mol) was dissolved in DCM(400 ml) and to this was added Potassium carbonate (34.7 g, 0.25 mol)followed by Methylamine (20.63 ml, 0.5 mol). Reaction was stirred atroom temperature under argon. Upon completion reaction was diluted withwater and extracted with DCM (3×) then dried over magnesium sulfate.Solvents were removed under reduced pressure to afford methyl2-(methylamino)-3-nitrobenzoate as a yellow solid.

Methyl 2-(methylamino)-3-nitrobenzoate (25.5 g, 0.121 mol) was dissolvedin acetic acid (100 ml) and DCM (40 ml). In a separate flask bromine(7.46 ml, 0.15 mol) was dissolved in acetic acid (15 ml). The firstsolution was then slowly added to the bromine solution via an additionfunnel and the reaction was stirred for 90 minutes. At this point thereaction was poured onto ice (200 g). After the ice had melted DCM wasadded and the reaction was extracted with DCM (3×), dried over magnesiumsulfate then solvents removed under reduced pressure to methyl5-bromo-2-(methylamino)-3-nitrobenzoate as a bright orange solid.

Methyl 5-bromo-2-(methylamino)-3-nitrobenzoate (20.1 g, 96.5 mmol),3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole(24.82 g, 111.25 mmol), PEPPSPI″-IPr catalyst (2.63 g, 3.86 mmol),Cesium carbonate (67.96 g, 208.59 mmol), 1,2-Dimethoxyethane (100 ml)and Water (30 ml) were mixed together and the solution degassed for 5minutes before heating to 110° C. for 1 hour. Reaction mixture was thencooled, diluted with EtAc and water and extracted EtAc (3×). Organicswere washed with water then brine, dried over sodium sulfate andevaporated to dryness under reduced pressure. Crude material purified bysilica gel chromatography using EtAc/Hex as the eluent to methyl5-(3,5-dimethylisoxazol-4-yl)-2-(methylamino)-3-nitrobenzoate (20.5 g,96%).

To methyl 5-(3,5-dimethylisoxazol-4-yl)-2-(methylamino)-3-nitrobenzoate(2000 mg, 6.55 mmol) was added stannous chloride (3726.66 mg, 19.65mmol) and Ethanol (100 ml) in a pressure tube. The suspension was thenheated in sealed vessel to 120° C. for 90 minutes at which point thereaction was cooled then stirred in a mixture of EtAc/1N NaOH for 1 houror until precipitates form. Precipitates were filtered and crude mixturewas diluted in EtAc and water and extracted 3× with EtAc. Organics werewashed with water then brine, dried over sodium sulfate and evaporatedto dryness under reduced pressure. Residue was purified by silica gelchromatography using MeOH/DCM as the eluent to afford methyl3-amino-5-(3,5-dimethylisoxazol-4-yl)-2-(methylamino)benzoate as a darkform (1.1 g, 61%)

Methyl 3-amino-5-(3,5-dimethylisoxazol-4-yl)-2-(methylamino)benzoate(1.1 g, 4 mmol) and 1,1′-carbonyldiimidazole (1.3 g, 7.99 mmol) werestirred in Tetrahydrofuran (100 ml) in a sealed pressure vessel Reactionwas heated to 100° C. and allowed to react overnight. Next day solventswere removed under reduced pressure. Material was slurried in minimalDCM, sonicated and filtered. Solids were air dried to afford methyl6-(3,5-dimethylisoxazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-4-carboxylateas an off-white powder (417 mg, 35%).

Methyl6-(3,5-dimethylisoxazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-4-carboxylate(410 mg, 1.36 mmol) was dissolved in THF (10 ml) and to this was addedDi-tert-butyl dicarbonate 97% (593.97 mg, 2.72 mmol) followed by4-(Dimethylamino)pyridine (33.25 mg, 0.27 mmol) and finallyTriethylamine (0.57 ml, 4.08 mmol). Reaction was allowed to stir at roomtemperature under argon for 3 hours, or until complete. Reaction wasthen diluted in EtAc and aqueous ammonium chloride and extracted withEtAc (3×). Organics were washed with ammonium chloride, water and brineand dried over sodium sulfate before evaporating to dryness. Crudematerial was purified by silica gel chromatography (EtAc/Hexanes as theeluent) to provide 1-tert-butyl 4-methyl6-(3,5-dimethylisoxazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1,4-dicarboxylateas an opaque oil.

Example 1575-(3,5-dimethylisoxazol-4-yl)-7-(hydroxydi(pyridin-2-yl)methyl)-1-methyl-1H-benzo[d]imidazol-2(3H)-one

To a dry, argon purged flask was added 5 mL THF and 2-bromopyridine(0.06 ml, 0.62 mmol). Reaction was cooled to −78° C. under argon andthen slowly was added 1.6M N-butyllithium in hexanes (0.43 ml) over 10minutes. Lithio species was allowed to form for 30 minutes at whichpoint 1-tert-butyl 4-methyl6-(3,5-dimethylisoxazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1,4-dicarboxylate(50 mg, 0.12 mmol) in 0.5 mL THF was added slowly. Reaction stirred at−78° C. for 5 minutes then allowed to warm. When reaction vessel neared0° C. was quenched with 1N HCl. Reaction was diluted with EtAc/H₂O andbasified with 1N NaOH until neutral. Mixture was extracted with EtAc(3×) then organics were washed with water then brine and dried oversodium sulfate. Solvents were removed under reduced pressure and crudemixture was purified by preparative HPLC to afford GS-650721 (110 mg,21%).

C₂₄H₂₁N₅O₃; 428.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H),8.57-8.50 (m, 2H), 7.89 (t, J=7.7 Hz, 2H), 7.55 (d, J=8.0 Hz, 2H), 7.39(t, J=6.1 Hz, 2H), 6.97 (d, J=1.7 Hz. 1H), 5.86 (d, J=1.7 Hz, 1H), 2.76(s, 3H), 2.18 (s, 3H), 1.97 (s, 3H).

Example 158 Example 159, and Example 160 f4-(cyclopentyl(hydroxy)methyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one4-(dicyclopentyl(hydroxy)methyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-oneand4-(cyclopentanecarbonyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one

To a mixture containing methyl6-(3,5-dimethylisoxazol-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-4-carboxylate(60 mg, 0.21 mmol, 1 equiv.) and THF (3 mL) is added cylopentylmagnesium chloride (0.88 mL, 1.46 mmol, 7 equiv.) at 0° C. for 5 min.After completion, the reaction was quenched and extracted with EtOAc andwashed with water, saturated NH₄Cl. After drying with MgSO4, it wasfiltered and concentrated to dryness. Purification was carried out byreverse phase HPLC.

1H NMR (400 MHz, Methanol-d4) δ 6.96 (d, J=1.5 Hz, 1H), 6.88 (d, J=1.6Hz, 1H), 4.66 (d, J=8.3 Hz, 1H), 2.39 (s, 3H), 2.24 (s, 3H), 1.93-1.80(m, 1H), 1.76-1.43 (m, 3H), 1.40 (s, 0H), 1.28 (d, J=8.3 Hz, 1H). LCMS(m/z+1) 328.38

1H NMR (400 MHz, Methanol-d4) δ 6.94-6.68 (m, 1H), 2.53 (s, 0H), 2.53(d, J=17.1 Hz, 1H), 2.38 (s, 2H), 2.23 (s, 2H), 1.84 (dd, J=12.4, 6.4Hz, 1H), 1.59-1.43 (m, 6H), 1.43-1.31 (m, 2H). LCMS (m/z+1) 396.49

1H NMR (400 MHz, Methanol-d₄) δ 7.59 (d, J=1.5 Hz, 1H), 7.19 (d, J=1.5Hz, 1H), 3.86 (t, J=7.8 Hz, 1H), 2.43 (s, 3H), 2.27 (s, 3H), 2.02-1.89(m, 4H), 1.71 (td, J=5.4, 3.3 Hz, 4H). LCMS (m/z+1) 326.36

Example 161 and Example 162(6-(3,5-dimethylisoxazol-4-yl)-4-(3-hydroxypentan-3-yl)-1H-benzo[d]imidazol-2(3H)-oneand methyl6-(3,5-dimethylisoxazol-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-4-carboxylate

Into a flask containing methyl6-(3,5-dimethylisoxazol-4-yl)-2-oxo-23-dihydro-1H-benzo[d]imidazole-4-carboxylate(60 mg, 0.21 mmol, 1 equiv.) is added cylopentylmagnesium chloride (0.88mL, 1.46 mmol, 7 equiv., 1M Hexanes) at 0° C. for 5 min. Aftercompletion, the reaction was quenched and extracted with EtOAc andwashed with water, saturated NH₄CL After drying with MgSO4, it wasfiltered and concentrated to dryness. Purification was carried out byreverse phase HPLC to GS-646013 and GS-646012.

1H NMR (400 MHz, Methanol-d4) δ 7.07-6.91 (m, 1H), 6.88 (d, J=1.6 Hz,1H), 2.39 (s, 3H), 2.23 (s, 3H), 1.81 (td, J=7.0, 3.6 Hz, 2H), 0.95 (t,J=7.4 Hz, 3H). LCMS (m/z+1) 288.15

1H NMR (400 MHz, Methanol-d4) δ 7.55 (d, J=1.6 Hz, 1H), 7.18 (d, J=1.6Hz, 1H), 3.97 (s, 3H), 2.40 (s, 3H), 2.24 (s, 3H). LCMS (m/z+1) 288.29

1H NMR (400 MHz, Methanol-d4) δ 6.86 (d, J=1.5 Hz, 1H), 6.74 (d, J=1.5Hz, 1H), 2.39 (s, 3H), 2.23 (s, 3H), 1.94 (dd, J=14.3, 7.3 Hz, 2H),1.90-1.74 (m, 2H), 0.82 (t, J=7.4 Hz, 7H). LCMS (m/z+1) 316.38

Example 163 and Example 1645-(3,5-dimethylisoxazol-4-yl)-1-methyl-7-(6-(trifluoromethyl)quinolin-7-yl)-1H-benzo[d]imidazol-2(3H)-oneand7-(6-(3,5-dimethylisoxazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-H-benzo[d]imidazol-4-yl)-6-(trifluoromethyl)quinoline1-oxide

To a microwave vial containing7-chloro-5-(3,5-dimethylisoxazol-4-yl)-1-methyl-1H-benzo[d]imidazol-2(3H)-one(100 mg, 0.36 mmol, 1 equiv.) was added5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)quinolone(350 mg, 1.08 mmol, 3 equiv.), Cs₂CO₃ (704 mg, 2.16 mmol, 6 equiv.) andPEPPSI™-IPr catalyst (98 mg, 0.14 mmol, 0.4 equiv.) and dissolved inDME-H₂O (4 mL, 0.2 M, 2/1, v/v). The mixture was heated to 120° C. for30 min in microwave. The reaction was concentrated in vacuo andpurification was carried out by reverse phase HPLC.

1H NMR (400 MHz, Methanol-d4) δ 9.03 (dd, J=4.2, 1.6 Hz, 1H), 8.32 (d,J=9.1 Hz, 1H), 8.19 (d, J=9.0 Hz, 1H), 7.97-7.76 (m, 1H), 7.56 (dd,J=8.6, 4.3 Hz, 1H), 7.16 (d, J=1.5 Hz, 1H), 6.91 (d, J=1.4 Hz, 1H), 2.74(s, 3H), 2.42 (s, 3H), 2.27 (s, 3H).

LCMS (m/z+1) 439.4

1H NMR (400 MHz, Methanol-d4) δ 9.19 (s, 1H), 8.30-8.17 (m, 1H),8.07-7.85 (m, 3H), 7.67 (ddd, J=8.3, 7.0, 1.2 Hz, 1H), 6.79 (d, J=1.3Hz, 1H), 5.88 (d, J=1.3 Hz, 1H), 3.81 (s, 3H), 2.05 (s, 3H), 1.86 (s,3H). LCMS (m/z+1) 455.26

Example 1654-(1-cyclopentyl-1-hydroxypropyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one

Into a flask containing the ketone (25 mg, 0.077 mmol, 1 equiv.) isadded ethyl magnesium bromide (0.28 mL, 0.28 mmol, 4 equiv., 1M) at 0°C. for 5 min. After completion, the reaction was quenched and extractedwith EtOAc and washed with water, saturated NH₄Cl. After drying withMgSO₄, it was filtered and concentrated to dryness. Purification wascarried out by reverse phase HPLC.

¹H NMR (400 MHz, Methanol-d₄) δ 6.85 (d, J=1.5 Hz, 1H), 6.78 (s, 1H),2.41 (d, J=16.9 Hz, 4H), 2.25 (d, J=17.0 Hz, 4H), 2.03-1.68 (m, 4H),1.50 (dtd J=29.4, 15.0, 13.9, 7.8 Hz, 5H), 0.76 (t, J=7.4 Hz, 41H). ¹⁹FNMR (376 MHz, DMSO-d) δ −136.97 (d, J=6.5 Hz). LCMS (M+1) 355.96

Example 1665-(3,5-dimethylisoxazol-4-yl)-4-fluoro-7-(6-methylquinolin-5-yl)-1H-benzo[d]imidazol-2(3H)-one

To a microwave vial containing7-chloro-5-(3,5-dimethylisoxazol-4-yl)-4-fluoro-1H-benzo[d]imidazol-2(3H)-one(16 mg, 0.057 mmol, 1 equiv.) was added 3,5-6-methylquinolin-5-ylboronicacid (53 mg, 0.28 mmol, 5 equiv.), Cs₂CO₃ (111 mg, 0.34 mmol, 6 equiv.)and PEPPSI™-IPr catalyst (7 mg, 0.0011 mmol, 0.2 equiv.) and dissolvedin DME-H₂O (20 mL, 0.2 M, 2/1, v/v). The mixture was heated to 140° C.After 2 h, the reaction was complete. After cooling, the reaction wasextracted with EtOAc and washed with water, saturated NH₄Cl. Afterdrying with MgSO₄, it was filtered and concentrated to dryness. Theresulting solid was washed with EtOAc. Purification was carried out byreverse phase HPLC to furnish5-(3,5-dimethylisoxazol-4-yl)-4-fluoro-7-(6-methylquinolin-5-yl)-1H-benzo[d]imidazol-2(3H)-one.

1H NMR (400 MHz, DMSO-d6) δ 11.42 (d, J=1.8 Hz, 1H), 10.63 (s, 1H), 8.82(dd, J=4.2, 1.6 Hz, 1H), 7.99 (d, J=8.6 Hz, 1H), 7.79-7.56 (m, 2H), 7.40(dd, J=8.5, 4.2 Hz, 1H), 6.77 (d, J=6.6 Hz, 1H), 2.34 (d, J=0.9 Hz, 3H),2.24 (s, 3H), 2.17 (d, J=0.9 Hz, 3H).

19F NMR (376 MHz, DMSO-d6) δ −136.97 (d, J=6.5 Hz). LCMS (m/z+1) 389.28

Example 167 and Example 168 (7R and7S)-5-(3,5-dimethylisoxazol-4-yl)-4-fluoro-7-(6-methylquinolin-5-yl)-1B-benzo[d]imidazol-2(3H)-one

The racemate of Example 166 was separated with super critical columnchromatography (JASCO SFC) using DAICEL AD-H (10 mm×250 mm, 20% MeOH, 15mL/min, 40° C., 15 atm). RT 2.733 min, 1.9 mg (GS-649951). RT 3.742 min,2.6 mg.

Example 1695-(3,5-dimethyloxazol-4-yl)-4-fluoro-7-(hydroxydi(pyridin-2-yl)methyl)-1H-benzo[d]imidazol-2(3H)-oneStep 1: Methyl 2-amino-5-(3,5-dimethylisoxazol-4-yl)-4-fluorobenzoate

To methyl 2-amino-5-bromo-4-fluorobenzoate (20 g, 80.6 mol.) and3,5-Dimethylisoxazole-4-boronic acid pinacol ester (24.2 g, 108.9 mol.,1.35 mmol) was added to a solvent mixture of 1,2-dimethoxymethane (120ml) and water (60 ml). To the above mixture were added PEPPSI-Ipr (3120mg, 4.2 mmol, 0.05 equiv.) and Cs₂CO₃ (78.8 g, 241 mol., 3 equiv.). Thereaction mixture was heated at 120° C. for 2 h in a pressure tube. Thereaction mixture was then diluted with EtOAc (100 ml), washed with bring(50 ml×2). The organic solvent was evaporated and the residue wasdissolved in DCM and purified with combi-flash column chromatography(product came out at 50% EtOAc/Hexane) to afford methyl2-amino-5-(3,5-dimethylisoxazol-4-yl)-4-fluorobenzoate.

1HNMR (400 MHz, Chloroform-d) δ 7.79 (dd, J=8.1, 1.2 Hz, 1H), 6.80-6.60(m, 1H), 3.90 (s, 4H), 2.34 (d, J=8.3 Hz, 4H), 2.20 (d, J=5.5 Hz, 4H).¹⁹F NMR (377 MHz, Chloroform-d) δ −96.83-−101.99 (m), −105.54 (d, J=13.8Hz). LCMS (m/z+1) 265.32.

Step 2: Methyl2-amino-5-(3,5-dimethylisoxazol-4-yl)-4-fluoro-3-nitrobenzoate

To a mixture of methyl2-amino-5-(3,5-dimethylisoxazol-4-yl)-4-fluorobenzoate (14 g, 53 mmol, 1equiv.) and TFA (100 mL) is slowly added nitronium tetrafluoroborate(9.1 g, 68.9 mmol, 1.3 equiv.). After completion, the mixture wasconcentrated under reduced pressure. The residue was dissolved and thenthe residue was dissolved in EtOAc (200 ml) and washed with brine (30ml×2). The organic solvent was evaporated. Methyl2-amino-5-(3,5-dimethylisoxazol-4-yl)-4-fluoro-3-nitrobenzoate was usedwithout further purification. ¹H NMR (400 MHz, Chloroform-d) δ 6.92 (d,J=5.8 Hz, 1H), 4.24 (s, 4H), 4.07-3.85 (m, 5H), 2.46-2.34 (m, 4H),2.31-2.22 (m, 5H).

19F NMR (377 MHz, Chloroform-d) δ −76.44, −121.12 (d, J=5.7 Hz). LCMS 20(m/z+1) 310.2

Step 3: Methyl2,3-diamino-5-(3,5-dimethylisoxazol-4-yl)-4-fluorobenzoate

Into a pressure tube containing N-methyl2-amino-5-(3,5-dimethylisoxazol-4-yl)-4-fluoro-3-nitrobenzoate (16.5 g,53.2 mol., 1 equiv.) is added EtOH (200 mL) and tin (II) chloride (20.2g, 107 mol., 2 equiv.). The reaction was heated for 3 h at 130° C. Thereaction was then stirred in 2N NaOH solution for 20 minutes beforebeing partitioned between water and ethyl acetate. The organic layer waswashed with brine and dried over sodium sulfate. Purification wascarried out by flash column chromatography to furnish methyl2,3-diamino-5-(3,5-dimethylisoxazol-4-yl)-4-fluorobenzoate (5700 mg,39%). LCMS (m/z+1) 270.2.

Step 4

A flask containing 2-bromopridine (135 μL, 1.37 mmol, 7 equiv.) and THF(3 mL) is cooled to −78° C. before BuLi (0.86 mL, 1.37 mmol, 7 equiv.)is added. After 30 min, methyl6-(3,5-dimethylisoxazol-4-yl)-7-fluoro-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-4-carboxylate(60 mg, 0.197 mmol, 1 equiv.) dissolved in THF (2 mL) is added to thereaction mixture. After completion, the reaction was quenched andextracted with EtOAc and washed with water, saturated NH₄Cl. Afterdrying with MgSO₄, it was filtered and concentrated to dryness.Purification was carried out by reverse phase HPLC.

1H NMR (400 MHz, Methanol-d4) δ 8.62 (dd, J=5.3, 1.6 Hz, 2H), 8.13 (t,J=8.0 Hz, 2H), 7.84 (d, J=8.1 Hz, 2H), 7.60 (dd, J=7.6, 5.3 Hz, 2H),6.43 (d, J=6.4 Hz, 1H), 2.24 (s, 3H), 2.07 (s, 3H). 19F NMR (377 MHz,Methanol-d4) δ −77.88, −137.06. LCMS (m/z+1) 431.92

Example 170 Example 171, and Example 1725-(3,5-dimethylisoxazol-4-yl)-4-fluoro-7-(hydroxydi(pyridin-2-yl)methyl)-1H-benzo[d]imidazol-2(3H)-one7-((1H-imidazol-1-yl)didin-2-yl)methyl)-5-(3,5-dimethylisoxazol-4-yl)-4-fluoro-1H-benzo[d]imidazol-2(3H)-oneand7-(di(pyridin-2-yl)methyl)-5-(3,5-dimethylisoxazol-4-yl)-4-fluoro-1H-benzo[d]imidazol-2(3H)-one

Alternatively, the title compound was made from(2,3-diamino-5-(3,5-dimethylisoxazol-4-yl)-4-fluorophenyl)di(pyridin-2-yl)methanol.Into a microwave vial containing(2,3-diamino-5-(3,5-dimethylisoxazol-4-yl)-4-fluorophenyl)di(pyridin-2-yl)methanol(50 mg, 0.12 mmol, 1 equiv.) is added THF (5 m) and CDI (30 mg, 0185mmol, 1.5 equiv.). The mixture was heated to 120° C. for 30 minutes in amicrowave reactor. The reaction was concentrated in vacuo and purifiedby HPLC.

1H NMR (400 MHz, Methanol-d4) δ 8.65 (ddt, J=5.4, 1.6, 0.7 Hz, 21),8.33-8.14 (m, 2H), 7.92 (dt, J=8.1, 0.9 Hz, 2H), 7.68 (ddt, J=7.3, 5.4,0.9 Hz, 2H), 6.39 (d, J=6.4 Hz, 1H), 2.24 (a, 4H), 2.06 (s, 4H). 19F NMR(377 MHz, Methanol-d4) δ −77.95, −136.55 (d, J=6.2 Hz).

LCMS (m/z+1) 431.92

1H NMR (400 MHz, Methanol-d4) δ 9.50 (t, J=1.5 Hz, 0H), 8.67 (ddd,J=4.8, 1.8, 0.9 Hz, 1H), 7.96-7.79 (m, 1H), 7.54 (t, J=1.8 Hz, 0H), 7.47(dd, J=7.7, 4.7, 0.9 Hz, 1H), 7.03 (dd, J=8.1, 1.0 Hz, 1H), 5.92 (d,J=6.3 Hz, 0H), 2.23 (d, J=0.9 Hz, 1H), 2.05 (d, J=0.9 Hz, 1H).

19F NMR (377 MHz, Methanol-d4) δ −77.74, −134.19 (d, J=6.2 Hz). LCMS(m/z+1) 482.17

1H NMR (400 MHz, DMSO-d6) 7.70 (dt, J=4.8, 1.3 Hz, 1H), 6.98 (td, J=7.8,1.9 Hz, 1H), 6.50 (ddd, J=7.6, 4.9, 1.1 Hz, 1H), 6.45 (d, J=7.9 Hz, 1H),5.83 (d, J=6.5 Hz, 1H), 5.16 (s, 1H), 1.44 (d, J=0.9 Hz, 2H), 1.27 (d,J=0.8 Hz, 2H). ¹⁹F NMR (377 MHz, DMSO-d6) δ −78.29, −128.15, −140.19 (d,J=6.3 Hz). LCMS (m/z+1) 416.19.

Example 173 and Example 1746-(3,5-dimethylisoxazol-4-yl)(3-hydroxy-2,4-dimethylpentan-3-yl-1H-benzo[d]imidazol-2(3H)-oneand6-(3,5-dimethylisoxazol-4-yl)-4-isobutyryl-1H-benzo[d]imidazol-2(3H)-one

Methyl6-(3,5-dimethylisoxazol-4-yl)-2-oxo-2,3-dihydro-H-benzo[d]imidazole-4-carboxylate(100 mg, 0.35 mmol) was dissolved in 5 mL of THF and stirred at roomtemperature followed by the addition of isopropylmagnesium bromide (0.87mL, 2.0 mmol). Addition Grignard was added in 1 hour intervals until thestarting material was consumed. Once complete, the crude reactionmixture was quenched with DI water and extracted 3× with ethyl acetate.Combined organic layers were washed with brine, dried over sodiumsulphate, filtered, concentrated in vacuo, and purified via HPLC.

C19H25N3O3; 344.2 (m/z+1). 1H NMR (400 MHz, cd3od) δ 6.88 (d, J=1.4 Hz,1H), 6.70 (s, 1H), 2.39 (s, 3H), 2.34 (dd, J=13.4, 6.7 Hz, 2H), 2.23 (s,3H), 0.91 (d, J=6.7 Hz, 6H), 0.85 (d, J=6.8 Hz, 6H).

C16H17N3O₃; 300.1 (m/z+1). ¹H NMR (400 MHz, cd₃od) δ 7.59 (s, 1H), 7.20(d, J=1.3 Hz, 1H), 3.68 (dt, J=13.6, 6.8 Hz, 1H), 2.43 (s, 3H), 2.27 (s,3H), 1.23 (d, J=6.8 Hz, 6H).

Example 1756-(3,5-dimethylisoxazol-4-yl)-4-(1-hydroxy-1-(pyridin-2-yl)pentyl)-1H-benzo[d]imidazol-2(3H)-one

A solution of tert-butyl6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-4-picolinoyl-1H-benzo[d]imidazole-1-carboxylatewas treated with n-BuLi (1.5 equiv) at −78° C. The reaction was stirredfor 15 minutes and quenched with 1M HCl, concentrated, dissolved inethanol (1 mL) and 4M HCl in dioxane (0.5 mL) and heated to 80° C. for 1h. The reaction mixture was concentrated and purified by reverse-phaseHPLC to give the desired product.

C22H24N4O3. 393.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 10.68 (s, 1H), 9.89(d, J=1.9 Hz, 1H), 8.56 (d, J=4.9 Hz, 1H), 7.88 (d, J=7.7 Hz, 2H), 7.37(s, 1H), 6.96 (d, J=1.6 Hz, 1H), 6.74 (d, J=1.5 Hz, 1H), 2.34 (m, 4H),2.15 (s, 3H), 1.37-1.22 (m, 4H), 1.22-1.01 (m, 1H), 0.80 (t, J=7.0 Hz,4H).

Example 176

A solution of tert-butyl6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-4-picolinoyl-1H-benzo[d]imidazole-1-carboxylate(360 mg, 0.79 mmol) and p-Toluenesulfonylmethyl isocyanide (183.95 mg,0.94 mmol) in methanol (5 mL) was stirred at room temperature overnight.The reaction mixture was concentrated and 1M aqueous HCl (3 mL) andconcentrated HCl (3 mL) was added. The reaction mixture was stirred for30 minutes, concentrated and purified by reverse-phase HPLC to give2-(6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazol-4-yl)-2-hydroxy-2-(pyridin-2-yl)acetaldehyde.

Ethyl magnesiumbromide (3M, 0.61 mL, 1.84 mmol) was added to a solutionof2-(6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazol-4-yl)-2-hydroxy-2-(pyridin-2-yl)acetaldehyde(120 mg, 0.31 mmol) in methyl-THF at 0° C. After 15 min, the reactionmixture was quenched with 1M HCl, concentrated and a portion of thismaterial was purified by reverse-phase HPLC to give the majordiastereomer4-(1,2-dihydroxy-1-(pyridin-2-yl)butyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one.

4-(1,2-dihydroxy-1-(pyridin-2-yl)butyl)-6-(3,5-dimethylisoxazol-4-yl)-H-benzo[d]imidazol-2(3H)-one.

C21H22N4O4. 395.1 (M+1). 1H NMR (400 MHz, DMSO-d₆) δ 10.73-10.59 (m,1H), 9.81 (s, 1H), 8.63 (d, J=4.7 Hz, 1H), 8.04 (s, 1H), 7.79 (d, J=7.9Hz, 1H), 7.50 (s, 1H), 7.11 (d, J=1.7 Hz, 1H), 6.77 (s, 1H), 4.39 (d,J=9.6 Hz, 1H), 2.34 (s, 3H), 2.15 (s, 3H), 1.40-1.14 (m, 2H), 0.86 (t,J=7.3 Hz, 3H).

Dess-Martin Periodinane (90 mg, 0.24 mmol) was added to a solution of4-(1,2-dihydroxy-1-(pyridin-2-yl)butyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one(50 mg, 0.12 mmol) in a mixture of dichlormethane and THF. The reactionwas stirred for 72 h at room temperature, concentrated and purified byreverse-phase HPLC. A portion of this product was dissolved inconcentrated HCl (0.1 mL) and ethanol (1 mL), heated at 80° C. for 3 hand concentrated to give6-(3,5-dimethylisoxazol-4-yl)-4-(1-hydroxy-2-oxo-1-(pyridin-2-yl)butyl)-1H-benzo[d]imidazol-2(3H)-one.

C21H20N4O4. 393.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 10.73 (s, 1H). 9.87(s, 1H), 8.62-8.39 (m, 1H), 7.89 (t, J=7.9 Hz, 1H), 7.61 (d, J=7.9 Hz,1H), 7.50-7.27 (m, 1H), 6.83 (s, 1H), 6.40 (s, 1H), 2.83 (dd, J=18.2,8.0 Hz, 2H), 2.27 (s, 3H), 2.07 (s, 3H), 0.91 (t, J=7.2 Hz, 3H).

Example 1776-(3,5-dimethyloxazol-4-yl)-4-(5,5-trifluoro-1,2-dihydroxy-1-(pyridin-2-yl)pentyl)-1H-benzo[d]imidazol-2(3H)-one

The following two diastereomers were likewise prepared usingtrifluoromethylethylmagnesium bromide in place of ethylmagnesiumbromide.

Major diastereomer C₂₂H₂₁F₃N₄O₄. 463.1 (M+1). ¹H NMR (400 MHz, DMSO-d₆)δ 10.67 (s, 1H), 9.80 (d, J=6.8 Hz, 1H), 8.59 (a, 1H), 7.91 (s, 1H),7.76 (s, 1H), 7.39 (s, 1H), 7.06 (s, 1H), 6.76 (s, 1H), 4.58 (d, J=9.9Hz, 1H), 2.40-2.50 (m, 2H), 2.42-2.30 (m, 3H), 2.13 (s, 3H), 1.48 (m,2H).

Minor diastereomer: C₂₂H₂₁F₃N₄O₄. 463.1 (M+1). ¹H NMR (400 MHz, DMSO-d₆)δ 10.59 (s, 1H), 10.03 (s, 1H), 8.56 (dd, J=5.4, 1.7 Hz, 1H), 7.52 (s,1H), 6.64 (d, J=1.6 Hz, 1H), 6.41 (s, 1H), 5.07 (s, 1H), 2.40 (m, 2H)2.17 (s, 3H), 1.99 (s, 3H), 1.65 (d, J=15.9 Hz, 2H).

Example 1786-(3,5-dimethylisoxazol-4-yl)-4-(2,2,3,3,3-pentafluoro-1-hydroxypropyl)-1H-benzo[d]imidazol-2(3H)-one

A solution of tert-butyl6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-4-formyl-1H-benzo[d]imidazole-1-carboxylate(100 mg, 0.26 mmol), pentafluoroiodoethane (350 mg, 1.42 mmol) and DMFwas cooled to −15° C. under nitrogen. Tetra(dimethylamino)ethylene wasadded (0.33 mL, 1.42 mmol) and the reaction mixture was irradiated witha sun lamp. A thick precipitate formed, and after 30 minutes, thereaction mixture was diluted with ethyl acetate filtered. The filtratewas washed with water and the organic layer was concentrated anddissolved in ethanol (3 mL) and 4M HCl in dioxane (1 mL) and heated to70° C. for 1 h. The reaction mixture was concentrated and purified byreverse-phase HPLC to give the desired product as a white powder.

C15H2F5N3O3. 378.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.02 (d, J=2.0Hz, 1H), 10.82 (s, 1H), 7.14-6.64 (m, 3H), 5.64-5.45 (m, 1H), 2.36 (s,3H), 2.18 (s, 3H).

Example 1796-(3,5-dimethylisoxazol-4-yl)-4-(2,2,2-trifluoro-1-hydroxyethyl)-1H-benzo[d]imidazol-2(3H)-one

The following compound was likewise prepared from trifluoroiodomethaneto give6-(3,5-dimethylisoxazol-4-yl)-4-(2,2,2-trifluoro-1-hydroxyethyl)-1H-benzo[d]imidazol-2(3H)-oneas a white powder.

C14H12F3N3O3. 328.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 10.95-10.85 (m,1H), 10.82 (d, J=1.9 Hz, 1H), 7.11-700 (m, 1H), 6.90 (dd, J=13.1, 3.6Hz, 2H), 5.43 (d, J=8.0 Hz, 1H), 2.35 (s, 3H), 2.17 (s, 3H).

Example 1804-(1,6-dihydroxy-2-oxo-1-(pyridin-2-yl)hexyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one

The following compound was isolated as a side product from the previousseries of reactions:

C₂₃H₂₄N₄O₅. 437.1 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ 10.74 (d, J=1.9 Hz,1H), 9.89 (d, J=1.9 Hz, 1H), 8.53 (dd, J=5.0, 1.5 Hz, 1H), 7.87 (td,J=7.7, 1.7 Hz, 1H), 7.60 (d, J=8.0 Hz, 1H), 7.37 (dd, J=7.5, 4.8 Hz,1H), 6.96 (s, 1H), 6.85-6.77 (m, 1H), 6.41 (d, J=1.5 Hz, 1H), 3.27 (t,J=6.5 Hz, 2H), 2.82 (ddd, J=17.9, 8.6, 6.2 Hz, 1H), 2.45-2.36 (m, 1H),2.26 (s, 3H), 2.07 (s, 3H), 1.55-1.34 (m, 2H), 1.29 (td, J=8.8, 4.6 Hz,2H).

Example 1816-(3,5-dimethylisoxazol-4-yl)-4-(2-ethoxy-1-hydroxy-1-(pyridin-2-yl)propyl)-1H-benzo[d]imidazol-2(3H)-one

Prepared analogously to give6-(3,5-dimethylisoxazol-4-yl)-4-(hydroxy(pyridin-2-yl)(tetrahydro-2H-pyran-2-yl)methyl)-1H-benzo[d]imidazol-2(3H)-oneusing ethyl vinyl ether in place of 2,3-dihydro-2H-pyran.

C22H24N4O4. 409.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 10.67 (d, J=2.1 Hz,1H), 9.72 (s, 1H), 8.69-8.55 (m, 1H), 7.87 (t, J=7.6 Hz, 1H), 7.73 (d,J=8.1 Hz, 1H), 7.36 (d, J=7.2 Hz, 1H), 7.15 (d, J=1.5 Hz, 1H), 6.77 (d,J=1.5 Hz, 1H), 4.50 (q, J=6.1 Hz, 1H), 3.62-3.44 (m, 1H), 3.26-3.09 (m,1H), 2.36 (s, 3H), 2.18 (s, 3H), 1.02-0.85 (m, 6H).

Example 1821-((2-(2-((6S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetyl)hydrazinyl)-6-oxohexyl)-3,3-dimethyl-2-((1E,3E,5E)-5-(1,3,3-trimethylindolin-2-ylidene)penta-1,3-die-1-yl)-3-indol-1-ium

2-((6S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)aceticacid (7 mg, 0.018 mmol) was dissolved in 1 ml DMF, to the solution wasadded HATU (10 mg, 0.027 mmol) and the reaction mixture was stirred atRT for 30 mins, then to the reaction mixture was added1-(6-hydrazinyl-6-oxohexyl)-3,3-dimethyl-2-((1E,3E,5E)-5-(1,3,3-trimethylindolin-2-ylidene)penta-1,3-dien-1-yl)-3H-indol-1-ium(5 mg, 0.009 mmol) at RT. The reaction was stirred at RT overnight. Thesolvent was then evaporated, the residue was purified with Prep HPLC toafford 3.6 mg product1-(6-(2-(2-((6S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetyl)hydrazinyl)-6-oxohexyl)-3,3-dimethyl-2-((1E,3E,5E)-5-(1,3,3-trimethylindolin-2-ylidene)penta-1,3-dien-1-yl)-3H-indol-1-ium.

C₅₁H₅₆ClN₈O₂S. 879.4 (M−1). ¹H NMR (400 MHz, CD₃OD) δ 7.18-7.10 (m, 2H),6.44-6.38 (m, 4H), 6.35-6.28 (m, 4H), 6.22-6.17 (m, 5H), 5.58-5.45 (m,1H), 5.23-5.17 (m, 2H), 3.62-3.58 (m, 1H), 3.08-2.97 (m, 2H), 2.58-2.52(m, 1H), 2.48 (s, 3H), 2.22 (s, 3H), 1.60 (s, 3H), 1.38 (s, 3H),1.23-1.20 (m, 2H), 0.82-0.65 (m, 4H), 0.62-0.60 (m, 12H), 0.54-0.48 (m,2H).

Example 1834-((6-(dimethylamino)pyridin-2-yl)(hydroxy)(pyridin-2-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one

A procedure similar to that used for6-(3,5-dimethylisoxazol-4-yl)-4-(hydroxy(6-methylpyridin-2-yl)(pyridin-2-yl)methyl)-1H-benzo[d]imidazol-2(3H)-one,using 6-bromo-2-N,N-dimethylaminopyridine as the starting material wasused to produce the intermediate (C₃₂H3N₆O₅, 585.2 (M+1)), which wastaken directly to the deprotection step to yield the title compound as ayellow oil.

C₂₅H₂₄N₆O₃. 457.1 (M+1). ¹H NMR (400 MHz, Chloroform-d) δ 8.78 (ddd,J=5.4, 1.7, 0.9 Hz, 1H), 8.30 (td, J=7.9, 1.7 Hz, 1H), 8.03 (dt, J=8.2,1.0 Hz, 1H), 7.87 (dd, J=8.9, 7.4 Hz, 1H), 7.78 (ddd, J=7.7, 5.3, 1.2Hz, 1H), 7.24 (t, J=7.5 Hz, 1H), 7.03 (d, J=1.5 Hz, 1H), 6.96 (dd,J=9.0, 0.8 Hz, 1H), 6.58 (d, J=1.5 Hz, 1H), 3.20 (s, 6H), 2.30 (s, 3H),2.13 (s, 3H).

Example 1846-(3,5-dimethylisoxazol-4-yl)-4-(hydroxy(pyridin-2-yl)(3-(trifluoromethyl)phenyl)methyl)-1H-benzo[d]imidazol-2(3H)-one

A procedure analogous to6-(3,5-dimethylisoxazol-4-yl)-4-(hydroxy(6-methylpyridin-2-yl)(pyridin-2-yl)methyl)-1H-benzo[d]imidazol-2(3H)-onewas used to synthesize the intermediate (C₃₂H₃₁F₃N₄O₅, 609.2 (M+1))which was immediately taken on to the deprotection step to yield ayellow solid.

C25H19F3N4O3. 481.1 (M+1). ¹H NMR (400 MHz, Methanol-d4) δ 8.77-8.69 (m,1H), 8.22 (td, J=7.9, 1.7 Hz, 1H), 7.76 (s, 1H), 7.72 (ddt, J=9.2, 6.6,3.1 Hz, 3H), 7.59 (t, J=7.8 Hz, 1H), 7.51 (d, J=8.1 Hz, 1H), 7.05 (d,J=1.5 Hz, 1H), 6.43 (d, J=1.5 Hz, 1H), 2.27 (s, 3H), 2.10 (s, 3H).

Example 1854-((4-chlorophenyl)(hydroxy)(pyridin-2-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one

A procedure similar to6-(3,5-dimethylisoxazol-4-yl)-4-(hydroxy(6-methylpyridin-2-yl)(pyridin-2-yl)methyl)-1H-benzo[d]imidazol-2(3H)-onewas used to synthesize the intermediate (C₃₁H₃₁ClN₄O₅, 575.2 (M+1))which was taken directly to the deprotection step to yield a yellowsolid (9.8 mg).

C₂₄H₁₉ClN₄O₃. 447.1 (M+1). ¹H NMR (400 MHz, Methanol-d₄) δ 8.71 (ddd,J=5.3, 1.7, 0.9 Hz, 1H), 8.19 (td, J=7.9, 1.7 Hz, 1H), 7.74-7.66 (m,2H), 7.44-7.38 (m, 2H), 7.33-7.28 (m, 2H), 7.03 (d, J=1.5 Hz, 1H), 6.48(d, J=1.5 Hz, 1H), 2.29 (s, 3H), 2.12 (s, 3H).

Example 1864-((6-aminopyridin-2-yl)(hydroxy)(pyridin-2-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one

In a 2-neck, 50-mL round-bottom flask, a solution of2-amino-6-bromopyridine (265.5 mg, 1.535 mmol) and1,2-bis(chlorodimethylsilyl)ethane (329.9 mg, 1.532 mmol) in2-methyltetrahydrofuran (12 mL) were cooled to −78° C. while stirringunder a nitrogen atmosphere. A solution of n-butyllithium (1.42 M inhexanes, 3.26 mL, 2.30 mmol) was added dropwise in 4 equal fractions(waiting five minutes in between) and the reaction mixture was stirredfor 30 minutes after the final addition. A solution of tert-butyl6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-4-picolinoyl-1H-benzo[d]imidazole-1-carboxylate(300.8 mg, 0.6504 mmol) in 2-methyltetrahydrofuran (1.5 mL) was addeddropwise. The reaction mixture was stirred for 45 minutes while warmingto room temperature or until reaction completion. The reaction mixturewas quenched with brine and diluted with ethyl acetate. The organiclayer was separated and saved and the aqueous layer was extracted withethyl acetate (three times, 40 mL each). The organic fractions werecombined, dried over MgSO₄, filtered and concentrated. The crude productwas taken directly to the deprotection step. C₂₅H₂₄N₆O₃. 457.2 (M+1).

The crude material was dissolved in ethanol (15 mL) and transferred to amicrowave vial. Hydrochloric acid was added (4M in dioxane, 1.6 mL, 6.4mmol) and the reaction vial was sealed and heated at 70° C. for 2 hours.The reaction mixture was cooled to room temperature and concentrated toyield a brown oil, which was triturated with dichloromethane. Theremaining oil was taken up in acetonitrile and concentrated to yield ayellow-white solid, which was further purified by preparatory HPLC toyield a yellow oil.

C₂₃H₂₀N₆O₃. 429.1 (M+1). Rf=0.2 in 20% MeOH:DCM. ¹H NMR (400 MHz,Methanol-d₄) δ 8.67 (ddd, J=5.0, 1.8, 0.9 Hz, 1H), 7.96 (td, J=7.8, 1.8Hz, 1H), 7.85 (dd, J=9.0, 7.4 Hz, 1H), 7.70 (dt, J=8.0, 1.0 Hz, 1H),7.47 (ddd, J=7.6, 4.8, 1.1 Hz, 1H), 7.04 (d, J=1.5 Hz, 1H), 6.97 (dd,J=9.0, 1.0 Hz, 1H), 6.66 (dd, J=7.4, 1.0 Hz, 1H), 6.42 (d, J=1.5 Hz,1H), 2.28 (s, 3H), 2.11 (s, 3H).

Example 1871-acetyl-4-((6-aminopyridin-2-yl)(hydroxy)(pyridin-2-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one

To a microwave vial capped with a septum, 4-(dimethylamino)pyridine (5.8mg, 0.047 mmol) and triethylamine (9 μL, 0.07 mmol) inN,N-dimethylformamide (0.5 mL) were cooled to 0° C. in a nitrogenatmosphere. Acetic anhydride (4.4 μL, 0.047 mmol) was added and thereaction mixture was stirred for 15 minutes at 0° C. before a solutionof4-((6-aminopyridin-2-yl)(hydroxy)(pyridin-2-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one(10 mg, 0.023 mmol) in N,N-dimethylformamide (0.25 mL) was addeddropwise to the reaction mixture. The reaction was allowed to warm toroom temperature and stirred for thirty minutes (or until completion).The reaction was quenched with water and diluted with ethyl acetate. Theorganic layer was separated and saved and the organic layer wasextracted with ethyl acetate (three times, 20 mL each). The organicfractions were collected, dried over MgSO₄, filtered and concentrated.The product was isolated by preparatory HPLC to yield a clear oil.

C₂₅H₂₂N₆O₄. 471.1 (M+1). ¹H NMR (400 MHz, Methanol-d₄) δ 8.68 (d, J=4.8Hz, 1H), 8.18 (d, J=1.6 Hz, 1H), 8.02-7.93 (m, 1H), 7.85 (dd, J=9.0, 7.4Hz, 1H), 7.72-7.65 (m, 1H), 7.52-7.43 (m, 1H), 6.98 (dd, J=9.2, 1.0 Hz,1H), 6.68-6.61 (m, 11H), 6.57 (d, J=1.6 Hz, 1H), 2.70 (s, 3H), 2.30 (s,3H), 2.11 (s, 3H).

Example 1884-((6-aminopyridin-2-yl)(hydroxy)(pyridin-2-yl)methyl)-1-(cyclopropanecarbonyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one

A procedure similar to 1-ace yl-4(6-aminopyridin-2-yl)(hydroxy)(pyridin-2-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)one was used.

C₂₇H₂₄N₆O₄. 497.2 (M+1). ¹H NMR (400 MHz, Methanol-d₄) δ 8.68 (ddd,J=4.9, 1.8, 0.9 Hz, 11H), 8.13 (d, J=1.6 Hz, 1H), 7.97 (td, J=7.8, 1.8Hz, 1H), 7.85 (dd, J=9.0, 7.4 Hz, 1H), 7.69 (dt, J=8.0, 1.0 Hz, 1H),7.48 (ddd, J=7.6, 4.8, 1.1 Hz, 1H), 7.25-7.08 (m, 2H), 6.98 (dd, J=8.9,1.0 Hz, 1H), 6.65 (dd, J=7.4, 1.0 Hz, 1K), 6.56 (d, J=1.6 Hz, 1H), 3.48(ddd, J=8.0, 4.6, 3.2 Hz, 1H), 2.29 (s, 3H), 2.10 (s. 3H), 1.21 (dt,J=5.2, 3.4 Hz, 2H), 1.15-1.06 (m, 2H).

Example 1896-(3,5-dimethylisoxazol-4-yl-4-(hydroxy(6-(methylamino)pyridin-2-yl)(pyridin-2-yl)methyl)-1H-benzo[d]imidazol-2(3H)-one

To a 50-mL, 2-neck round-bottom flask, 6-bromo-N-methylpyridin-2-amine(41.5 mg, 0.222 mmol) and chlorotrimethylsilane (29 μL, 0.23 mmol) weredissolved in tetrahydrofuran (2 mL). The cloudy white suspension wasstirred under nitrogen for thirty minutes at room temperature. Thereaction mixture was then cooled to −78° C. before a 1.6 Mn-butyllithium solution in hexanes (0.23 mL, 0.37 mmol) was addeddropwise and the solution was stirred for thirty minutes. A solution oftert-butyl6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-4-picolinoyl-1H-benzo[d]imidazole-1-carboxylatein tetrahydrofuran (1 mL) was added dropwise and the reaction was warmedto ambient temperature and stirred for twenty minutes or until reactioncompletion. The reaction mixture was quenched with brine and dilutedwith ethyl acetate. The organic layer was separated and saved and theaqueous layer was neutralized and subsequently extracted with ethylacetate twice. The combined organic fractions were dried over sodiumsulfate, decanted and concentrated. The crude intermediate was takendirectly to the deprotection step. C₃₁H₃₄N₆O₅. 611.3 (M+1).

In a microwave vial, the crude intermediate was dissolved in ethanol (3mL) and 4M hydrochloric acid in dioxane (1 mL) was added. The vial wassealed and heated at 65° C. for 1 hour. The reaction mixture wasconcentrated, filtered and the title compounds was purified viapreparatory HPLC to yield a yellow solid.

CH₄H₂₂N₆O₃. 443.1 (M+1). ¹H NMR (400 MHz, Methanol-d₄) δ 8.70 (ddd,J=5.0, 1.8, 0.9 Hz, 1H), 8.03 (td, J=7.8, 1.7 Hz, 1H), 7.90 (dd, J=9.0,7.4 Hz, 1H), 7.81 (d, J=8.0 Hz, 1H), 7.53 (ddd, J=7.6, 4.9, 1.1 Hz, 1H),7.02 (d, J=1.5 Hz, 1H), 7.00 (d, J=8.8 Hz, 1H), 6.87 (d, J=7.4 Hz, 1H),6.48 (d, J=1.5 Hz, 1H), 3.06 (s, 3H), 2.28 (s, 3H), 2.10 (s, 3H).

Example 1904-((6-bromo-3-fluoro-2-methylpyridin-4-yl)(hydroxy)(pyridin-2-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one

To a solution of 2-bromo-5-fluoro-6-methyl-2-pyridine (411 mg, 2.16mmol) in THF (10 mL) was added BuLi (0.86 mL, 2.16 mmol, 2.5 M in THF)and the solution was stirred at −78° C. for 1 h. To the solution oftert-butyl6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-4-picolinoyl-1H-benzo[d]imidazole-1-carboxylate(200 mg, 0.43 mmol) in THF (5 mL) was added the solution of the lithiateand the solution was stirred at −78° C. for 1 h. Aq NH₄Cl was added andthe solution was extracted with EtOAc (200 mL). The organic solution waswashed with brine and dried over Na₂OS₄. Solvent was removed and theresidue was dissolved in EtOH (6 mL) with 0.8 mL of 4N HCl in dioxane.The solution was heated at microwave at 70° C. for 1 h. Solvent wasremoved and the residue was purified by HPLC to give4-((6-bromo-3-fluoro-2-methylpyridin-4-yl)(hydroxy)(pyridin-2-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one

C₂₄H₁₉BrFN₅O₃. MS m/z 523.9 (M+1).

Example 1916-(3,5-dimethylisoxazol-4-yl)-4-((3-fluoro-2-methylpyridin-4-yl)(hydroxy)(pyridin-2-yl)methyl)-1H-benzo[d]imidazol-2(3H)-one

A mixture of4-(6-bromo-3-fluoro-2-methylpyridin-4-yl)(hydroxy)(pyridin-2-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)one obtained above and Pd/C (5% 100 mg) in MeOH (10 mL) was stirredunder H₂ balloon for 1 h. Reaction mixture was filtered and the filtratewas concentrated to dryness. The residue was purified by HPLC to give6-(3,5-dimethylisoxazol-4-yl)-4-((3-fluoro-2-methylpyridin-4-yl)(hydroxy)(pyridin-2-yl)methyl)-1H-benzo[d]imidazol-2(3H)-one.

C₂₄H₂₀FN₅O₃. MS m/z 446.02 (M+1). ¹H NMR (400 MHz, Methanol d) δ 8.56(ddd, J=5.1, 1.8, 0.9 Hz, 1H), 8.42 (di, J=5.6 Hz, 11H), 8.00 (td,J=7.8, 1.7 Hz, 1H), 7.76-7.64 (m, 2H), 7.49 (ddd, J=7.6, 5.0, 1.1 Hz,1H), 7.02 (d, J=1.5 Hz, 11H), 6.59 (t, J=1.8 Hz, 1H), 2.53 (d, J=3.0 Hz,3H), 2.30 (s, 3H), 2.13 (s, 3H).

Example 192 4-(3,5-dimethylisoxazol-4-yl)-2-nitroaniline

To a mixture of 4-bromo-2-nitro-phenylamine (150 g, 0.691 mol, 1.0 eq)and 3,5-dimethylisoxazole-4-boronic acid pinacol ester (169 g, 0.725mol, 1.05 eq) in 1,2-dimethoxyethane (1.5 L) and water (700 mL) wereadded PdCl₂(dppf) (56 g, 69 mmol, 0.1 eq) and K₂CO₃ (190 g, 1.38 mol,2.0 eq). The reaction mixture was heated at 95° C. overnight. Thereaction mixture was diluted with EtOAc (3 L), washed with brine (2×500mL). The organic solvent was evaporated and the residue was purifiedwith flash chromatography on silica (PE/EA=10:1-1:1) to give 150 g4-(3,5-dimethylisoxazol-4-yl)-2-nitroaniline as a red solid.

C₁₁H₁₁N₃O₃. 234.2 (M+1)

Example 193 4-(3,5-dimethylisoxazol-4-yl)-2-Iodo-6-nitroaniline

To a solution of compound 4-(3,5-dimethylisoxazol-4-yl)-2-nitroaniline(334 g, 1.43 mol, 1.0 eq) in ethanol (3.3 L) were added iodine (726 g,2.8 mol, 2.0 eq) and silver nitrate (485 g, 2.8 mol, 2.0 eq). Thereaction mixture was stirred at rt overnight, filtered, and the filtratewas evaporated to dryness. The residue was dissolved in EtOAc (5 L) andwashed with water and brine, and dried over sodium sulfate. The organicsolvent was evaporated to give a residue, which was purified by flashcolumn chromatography on silica gel (PE/EA=4:1-3:1) to give compound 393g of 4-(3,5-dimethylisoxazol-4-yl)-2-iodo-6-nitroaniline as an orangesolid.

C₁₁H₁₀IN₃O₃. 360.1 (M+1)

Example 194 5-(3,5-dimethylisoxazole-4-yl)-3-iodobenzene-1,2-diamine

To a solution of 4-(3,5-dimethylisoxazol-4-yl)-2-iodo-6-nitroaniline(393 g, 1.09 mol, 1.0 eq) in ethanol (4 L) was added tin (II) chloride(1.03 kg, 5.46 mol, 5.0 eq). The reaction mixture was stirred at 75° C.for 10 h. The solvent was evaporated and the residue was dissolved inEtOAc (5 L), washed with 1 N sodium hydroxide (3×1 L) (the solidprecipitated out should be filtered). The organic phase was dried overNa₂SO₄ and the solvent was removed to give a residue. The residue waspurified by flash chromatography on silica (PE/EA=2:1-3:2) to give 253 gof 5-(3,5-dimethylisoxazol-4-yl)-3-iodobenzene-1,2-diamine as a slightlybrown solid.

C₁₁H₁₂IN₃O. 330.1 (M+1)

Example 1956-(3,5-dimethylisoxazol-4-yl)-4-iodo-1H-benzo[d]imidazol-2(3H)-one

5-(3,5-dimethylisoxazol-4-yl)-3-iodobenzene-1,2-diamine (253 g, 0.77mol, 1.0 eq) was treated with carbonyl diimidazole (187 g, 1.15 mol, 1.5eq) and DMAP (47 g, 384 mmol, 0.5 eq) in THF (2.5 L) at 80° C. for 16 h.The precipitate was obtained by filtration. The solid was trituratedwith EA/PE (1/1) to give 197 g of6-(3,5-dimethylisoxazol-4-yl)-4-iodo-1H-benzo[d]imidazol-2(3H)-one as awhite solid.

C₁₂H₁₀IN₃O₂ 356.1 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ 10.97 (s, 1H),10.91 (s, 1H), 7.23 (s, 1H), 5.86 (s, 1H), 2.35 (s, 3H), 2.17 (s, 3H).

Example 1966-(3,5-dimethyloxazol-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2(3H)-one

A mixture of6-(3,5-dimethylisoxazol-4-yl)-4-iodo-1H-benzo[d]imidazol-2(3H)-one (166g, 468 mmol 1.0 eq), Pd(dppf)C₂ (19 g, 5% mol), KOAc (92 g, 935 mmol, 2eq) and bispinacolato diboron (237 g, 935 mmol, 2.0 eq) in degasseddioxane (3.5 L) was flushed with nitrogen. The reaction mixture washeated at 120° C. under N₂ overnight. Then the reaction mixture wasconcentrated and dry-loaded onto silica gel and purified by flashchromatography (PE/EA=10:1-3:1) to give 72 g of6-(3,5-dimethylisoxazol-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2(3H)-one.

C₁₈H₂₂BN₃O₄. 356.0 (M+1) ¹H NMR (400 MHz, DMSO-d₆) δ 10.78 (s, 1H), 9.84(s, 1H), 7.04 (s, 1H), 6.97 (s, 1H), 2.34 (s, 3H), 2.16 (s, 3H).

Example 197 4-(3,5-dimethylisoxazol-4-yl)-2-nitroaniline

4-bromo-2-nitroaniline (1 g, 4.6 mmol) and3,5-Dimethylisoxazole-4-boronic acid pinacol ester (2 g, 9.2 mmol) wasadded to a solvent mixture of 1,2-dimethoxymethane (12 ml) and water (6ml). To the above mixture were added PEPPSI-Ipc (312 mg, 0.46 mmol) andCsCO₃ (4.5 g, 13.8 mmol). The reaction mixture was heated at 120° C. for30 min. The reaction mixture was then diluted with EtOAc (100 ml),washed with bring (50 ml×2). The organic solvent was evaporated and theresidue was dissolved in DCM and purified with flash columnchromatography (50% EtOAc/Hexane) to afford4-(3,5-dimethylisoxazol-4-yl)-2-nitroaniline.

Example 198 4-(3,5-dimethylisoxazol-4-yl)-2-iodo-6-nitroaniline

4-(3,5-dimethylisoxazol-4-yl)-2-nitroaniline (1 g, 4.6 mmol) was addedto EtOH (50 ml), to the mixture was added I₂ (1.4 g, 5.5 mmol) andAgNCO₃ (0.94, 5.5 mmol). The reaction mixture was stirred at roomtemperature overnight. The solvent was evaporated and then the residuewas dissolved in EtOAc (50 ml) and washed with brine (30 ml×2). Theorganic solvent was evaporated and the residue was dissolved in DCM andpurified with flash column chromatography (product came out at 35%EtOAc/Hexane) to afford4-(3,5-dimethylisoxazol-4-yl)-2-iodo-6-nitroaniline.

Example 199 5-(3,5-dimethylisoxazol-4-yl)-3-iodobenzene-1,2-diamine

4-(3,5-dimethylisoxazol-4-yl)-2-iodo-6-nitroaniline (0.9 g, 2.5 mmol)was to added a EtOH (50 ml), to the mixture were added SnCl₂ (2.4 g,12.5 mmol). The reaction mixture was stirred at 75° C. for 7 h. Thesolvent was evaporated and then the residue was dissolved in EtOAc (100ml) and washed with 1N NaOH (100 ml×3). The organic solvent wasevaporated and the residue was dissolved in DCM and purified withcombi-flash column chromatography (product came out at 60% EtOAc/Hexane)to afford 5-(3,5-dimethylioxazol-4-yl)-3-iodobenzene-1,2-diamine. LCMSm/z [M+H]⁺ C11H12IN₃O requires: 330.00. Found 330.03 ¹H NMR (400 MHz,CD₃OD) δ2.21 (s, 3H), 2.39 (s, 3H), 7.16 (d, 1H), 7.62 (d, 1H).

Example 2006-(3,5-dimethylisoxazol-4-yl)-4-iodo-1H-benzo[d]imidazol-2(3H)-one

A mixture of 5-(3,5-dimethylisoxazol-4-yl)-3-iodobenzene-1,2-diamine (15g, 45.6 mmol, 1.0 eq), DMAP (2.9 g, 22.7 mmol, 0.5 eq) and carbonyldiimidazole (11.0 g, 68.4 mmol, 1.5 eq) in THF (200 mL) was refluxed for3 h. The reaction was cooled to room temperature, purified by flashcolumn chromatography to give a solid, which contained some imidazoleand DMAP. The solid was triturated with THF (2×) and filtered to afford6-(3,5-dimethylisoxazol-4-yl)-4-iodo-1H-benzo[d]imidazol-2(3H)-one.LC-MS: 354.0 [M−H]⁻ ¹H NMR (400 MHz, DMSO-d6) δ 10.9 (br s, 2H), 7.24(d, J=1.6 Hz, 1H), 6.97 (d, J=1.6 Hz, 1H), 2.37 (s, 3H), 1.78 (s, 3H).

Example 201 Biochemical Alpha Assay

Binding of the bromodomain BRD4_I to an acetylated histone H4 peptidewas measured using a bead based Amplified Luminescent ProximityHomogeneous Assay (ALPHA). The synthetic peptide containing amino acids1-18 of histone H4 was acetylated at lysine 5, 8, 12, 16 and conjugatedto biotin (SGRGACKGGACKGLGACKGGAACKRH-GSGSK-biotin) was purchased fromMillipore. BRD4_I was expressed and purified from Escherichia coli as anN-terminal Hiss-tagged protein. Nickel-Chelate ALPHA acceptor beads(Perkin Elmer) were used to specifically bind BRD4_(—)1 and ALPHAstreptavidin donor beads (Perkin Elmer) were used because theyspecifically recognized the biotinylated H4 peptide. Binding ofBRD4_(—)1 to the peptide resulted in proximity of the donor and acceptorbeads which leads to an increase in ALPHA signal whereas disruption ofthis protein-peptide interaction with a small molecule inhibitorresulted in a decrease in ALPHA signal. Assays were performed in 50 mMHepes (pH 7.5), 150 mM NaCl, 0.1 mg/ml BSA, 0.01% (v/v) Brij, 0.5% (v/v)DMSO, 200 nM H4 peptide and 15 nM of BRD4_(—)1 protein. After an assayreaction time of 60 minutes at 25° C., binding was measured with 20 g/mlstreptavidin donor beads and 20 μg/ml nickel-chelate acceptor beads.ALPHA signal was detected on an Envision plate reader (Ex: 320 nm; Em:570 nm; Ex time: 180 ms). Data were normalized based on a positive (2 μMI-BET) and negative (DMSO) controls and IC₅₀ values were calculated fromthe fit of the dose-response curves to a four-parameter equation. AllIC₅₀ values represent geometric mean values of a minimum of fourdeterminations. These assays generally produced results within 3-fold ofthe reported mean.

Biochemical HTRF Assay

Binding of the two tandem bromodomains, BRD4 I and BRD4_(—)2, to anacetylated histone H4 peptide were measured using a homogeneous timeresolved fluorescence resonance energy transfer (TR-FRET) assay. Thesynthetic peptide containing amino acids 1-18 of histone H4 wasacetylated at lysine 5, 8, 12, 16 and conjugated to biotin(SGRGACKGGACKGLGACKGGAACKRH-GSGSK-biotin) was purchased from Millipore.BRD4_I and BRD4_(—)2 were expressed and purified from Escherichia colias N-terminal His₆-tagged proteins. An XL665 labeled anti-His antibody(Cisbio) was used to specifically bind BRD4 and a cryptate labeledstreptavidin protein was used because it specifically recognized thebiotinylated H4 peptide. Binding of BRD4 to the peptide resulted in anincrease in FRET signal whereas disruption of this protein-peptideinteraction with a small molecule inhibitor resulted in a decrease inFRET signal. Assays were performed in 50 mM Hepes (pH 7.5), 150 mM NaCl,0.1 mg/ml BSA, 0.01% (v/v) Brij, 0.5% (v/v) DMSO and 200 nM H4 peptideat the following concentrations for each BRD4 isoform: 60 nM BRD4_(—)1and 120 nM BRD4_(—)2. After an assay reaction time of 60 minutes at 25°C., binding was measured with 2 nM cryptate labeled streptavidin and 10nM anti-His-XL665 antibody. TR-FRET signal was detected on an Envisionplate reader (Ex: 320 nm; Em: 615/665 nm; 100 μs delay and 200 μs readwindow). Data were normalized based on a positive (2 μM I-BET) andnegative (DMSO) controls and IC₅₀ values were calculated from the fit ofthe dose-response curves to a four-parameter equation. All IC₅₀ valuesrepresent geometric mean values of a minimum of four determinations.These assays generally produced results within 3-fold of the reportedmean.

BRD4-1 Ligand KI and BRD4-2 Ligand KI Assays:

Binding of the two tandem bromodomains, BRD4-I and BRD4-2, to a Cy5labeled probe/ligand (Compound 201-A) were measured using a homogeneoustime resolved fluorescence resonance energy transfer (TR-FRET) assay.

The labeled ligand specifically binds BRD4-1 and BRD4-2 and can bedisplaced by a small molecule inhibitor that shares a similar oroverlapping binding site. BRD4-I and BRD4-2 were expressed and purifiedfrom Escherichia coli as N-terminal His₆-tagged proteins. A Eu-cryptatelabeled anti-His antibody (Perkin Elmer) was used to specifically bindBRD4. Binding of BRD4 to the labeled probe/ligand resulted in anincrease in FRET signal whereas displacement of this labeled ligand fromBRD4 with a small molecule inhibitor resulted in a decrease in FRETsignal. Assays were performed in 50 mM Hepes (pH 7.5), 150 mM NaCl, 0.1mg/ml BSA, 0.01% (v/v) Brij, 0.5% (v/v) DMSO and 10 nM labeled ligand atthe following concentrations for each BRD4 isoform: 2 nM BRD4-1 and 0.5nM BRD4-2. After an assay reaction time of 60 minutes at 25° C., bindingwas measured with 2 nM Eu-cryptate labeled anti-His antibody. TR-FRETsignal was detected on an Envision plate reader (Ex: 320 nm; Em: 615/665nm; 100 μs delay and 200 μs read window). Data were normalized based ona positive (2 μM I-BET) and negative (DMSO) controls and IC50 valueswere calculated from the fit of the dose-response curves to afour-parameter equation. All IC50 values represent geometric mean valuesof a minimum of four determinations. The IC50 values were converted toKi values (dissociation constant for BRD4-inhibitor complex) using theCheng and Prusoff equation for a competitive inhibitor mode of action.These assays generally produced results within 3-fold of the reportedmean.

MT-4 Proliferation Assay in 384-Well Format

Compounds were tested in a standardized high-throughput 384-well assayformat. Each compound was serially diluted 3-fold in 100% DMSO inpolypropylene 384-well plates using a Biomek FX Workstation, and 0.4 μLcompound added to an assay plate containing 40 μL RPMI media. Compoundswere arranged in a horizontal pattern, with 10 concentrations percompound, and 8 compounds added per plate. Due to low DMSO tolerability,the final DMSO concentration never exceeded 0.5% (v/v). Each assay platecontained 10 μM Puromycin and 0.5% DMSO in RPMI-1640 as positive andnegative controls respectively. MT-4 cells (HTLV-1 transformed, human Tlymphoblastoid cells, NIH Aids Reagent program) were added in volumes of35 μL per well and 2,000 cells per well using a Biotek uFlow Workstation(Biotek, Winooski, Vt.), and the plates subsequently incubated for 5days at 37° C. in an incubator set at 5% CO2 and 90% humidity.

After 5 days, 22 μL Cell Titer Glo (Promega) was added to the assayplates with a Biotek uFlow Workstation. Plates were subsequently placedon a Perkin Elmer Envision Plate Reader for 5 minutes before theluminescence signal was read. CC₅₀ values were calculated from thecompound concentration that caused a 50% decrease in luminescencesignal, a measure of toxicity, and calculated by non-linear regressionusing Pipeline Pilot software (Accelrys, San Diego, Calif.).

c-Myc Down Regulation and Viability Assays

An enzyme linked immunosorbent assay using the Meso Scale Diagnostic(MSD) technology was used to detect levels of c-Myc produced in MM1Scells (ATCC). MM1S cells were cultured in RPMI-1640 media (Corning),supplemented with 10% FBS (Hyclone), 1% penicillin-streptomycin(Cellgro), 2-mercaptoethanol (Gibco) and seeded onto 384-tissue culturetreated filter binding plates (Millipore) at a density of 40K cells/wellcontaining titrations of small molecule inhibitors or DMSO (0.4%) in avolume of 100 μl of media. After an incubation time of 24 hrs, cellswere lysed (1× lysis buffer (Thermo) supplemented with protease andphosphatase inhibitor cocktail (Thermo)) and the plates centrifuged(1000 rpm, 1 min) to capture c-Myc on MSD plates coated with amonoclonal c-Myc antibody (Origene). Assay wells were washed (3×Invitrogen wash buffer) and probed with a polyclonal c-Myc antibody(Abcam) and MSD detection antibody solution in order to detect levels ofc-Myc on the MSD platform. c-Myc capture was reported in pg/ml based ona standard curve using recombinant c-Myc protein (Prosci). EC50 valueswere calculated from the fit of the dose-response curves to afour-parameter equation. All EC50 values represent geometric mean valuesof a minimum of four determinations. These assays generally producedresults within 3-fold of the reported mean.

For cell viability in the MM1S cell line, cells were seeded onto384-tissue culture treated plates (Greiner) at a density of 60Kcells/well containing titrations of small molecule inhibitors or DMSO(0.2%). After 72 hr incubation cells were analyzed for cell viability byaddition of CellTiter Glo (Promega) to the assay plates. After 15 minincubation at room temperature the signal from the viable cells wasanalyzed on an Envision plate reader (Perkin Elmer). EC50 values werecalculated from the fit of the dose-response curves to a four-parameterequation. All EC50 values represent geometric mean values of a minimumof four determinations. These assays generally produced results within3-fold of the reported mean.

Results are shown in Tables 1 and 2. An “n/a” indicates that assay wasnot performed for that compound.

TABLE 1 Com- pound IC₅₀ IC₅₀ of BRD4_ HTBS HTBS CC₅₀ Exam- 1- BRD4-1BRD4-2 MT4 ple ALPHA HTRF HTRF 384 No. Structure [nM] [nM] [nM] [nM]  1

n/a 1412 1068 1123.8  2

30.8 135 119 18.951  3

119.4 295 n/a 196.26  4

37.2 119 141 102.76  5

233.5 350 144 232.94  6

46.8 132 108 53.911  7

37.3 121 101 17.543  8

240.6 511 168 116.58  9

270.3 497 227 203.9 10

196.5 313 396 1027.6 11

222 438 174 420.62 12

232.7 316 314 761.13 13

45.2 n/a n/a 51.551 14

14 n/a n/a 9.543

TABLE 2 BRD4-1 CC₅₀ Compound Ligand BRD4-1 MT4 of K1 Ligand 384 cMYCExample No. Structure [nM] K2 [nM] [nM] EC₅₀ [nM]  23

12.9 3.0 9.1 13.2  33

14.1 5.3 29.1 176.5  36

14.1 5.3 29.1 176.5  38

7.8 4.4 29.7 84.7  39

11.8 5.9 42.1 127.7  41

12.8 5.0 47.3 104.0  49

8.1 2.7 9.7 n/a  50

8.7 5.9 16.0 n/a  52

8.9 6.4 36.1 134.9  53

26.6 24.1 28.6 171.7  54

22.7 14.1 27.1 111.2  55

14.5 18.2 41.0 141.2  56

6.0 3.6 24.8 40.9  73

34.2 24.0 61.0 153.6 133

40.3 15.8 25.5 44.3 134

69.9 5.3 19.1 74.4 140

35.2 43.8 78.3 216.7 143

29.3 8.0 20.4 118.2 144

7.7 2.7 n/a n/a 147

81.6 16.0 56.5 107.3 149

17.3 4.6 17.5 73.8 169

62.0 33.5 41.4 128.2

While the foregoing description describes specific embodiments andaspects, those with ordinary skill in the art will appreciate thatvarious modifications and alternatives can be developed. Accordingly,the particular embodiments and aspects described above are meant to beillustrative only, and not to limit the scope of the invention, which isto be given the full breadth of the appended claims, and any and allequivalents thereof.

We claim:
 1. A compound of Formula (I)

wherein R^(1a) and R^(1b) are each independently C₁-C₆ alkyl, C₁-C₆alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, C₁-C₆ hydroxyalkyl, C₃-C₆cycloalkyl, or CH₂—C₃-C₆ cycloalkyl; R^(2a) and R^(2b) are eachindependently H or halogen; R³ is C₅-C₁₀ aryl, C₅-C₁₀ heteroaryl, orC₅-C₁₀ heteroarylalkyl, each of which is optionally substituted withfrom 1 to 5 R²⁰ groups; or —S(O)₂NHR⁴, wherein R⁴ is C₁-C₆ alkyl orC₃-C₇ cycloalkyl, each of which is optionally substituted with from 1 to5 R²⁰ groups; or a moiety of the formula

wherein R⁶ is H, OH, or halogen; and R⁷ and R⁸ are each independentlyC₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₁-C₆heteroalkyl, C₅-C₁₂ aryl, C₅-C₁₂ heteroaryl, or C₅-C₁₂ heteroarylalkyl,each of which is optionally substituted with from 1 to 5 R²⁰ groups; orR⁶ is H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl,phenyl, naphthyl, or C₃-C₁₂ heteroaryl; and R⁷ and R⁸ together form aC₁-C₆ alkylidene group having a double bond with the carbon to whicheach of R⁶, R⁷, and R⁸ are bound wherein each of the C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, —C₃-C₆ cycloalkyl, phenyl, naphthyl, or C₃-C₁₂heteroaryl groups is optionally substituted with from 1 to 5 R²⁰ groups;X is N-Q, or O; Q is H, C₁-C₃ alkyl, C₁-C₃ haloalkyl, benzyl orsubstituted benzyl; each R²⁰ is independently C₁-C₆ alkyl, C₃-C₆cycloalkyl, C₁-C₆ heteroalkyl, C₃-C₆ heterocyclic, C₅-C₁₂ aryl, C₅-C₁₂heteroaryl, halogen, oxo, —OR^(a), —C(O)R^(a), —C(O)OR^(a),—C(O)NR^(a)R^(b), —OC(O)NR^(a)R^(b), —NR^(a)R^(b), —NR^(a)C(O)R^(b),—NR^(a)C(O)OR^(b), —S(O)₀₋₂R^(a), —S(O)₂NR^(a)R^(b), —NR^(a)S(O)₂R^(b),—Ni, —CN, or —NO₂, wherein each C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₁-C₆heteroalkyl, C₃-C₆ heterocyclic, C₅-C₁₂ aryl, C₅-C₁₂ heteroaryl isoptionally substituted with from one to five halogen, oxo, —OR^(a),—C(O)R^(a), —C(O)OR^(a), —C(O)NR^(a)R^(b), —OC(O)NR^(a)R^(b),—NR^(a)R^(b), —NR^(a)C(O)R^(b), —NR^(a)C(O)OR^(b), —S(O)₀₋₂R^(a),—S(O)₂NR^(a)R^(b), —NR^(a)S(O)₂R^(b), —N₃, —CN, or —NO₂; each R^(a) andR^(b) is independently H; or C₁-C₆ alkyl C₃-C₆ cycloalkyl, C₁-C₆heteroalkyl, C₃-C₆ heterocyclic, C₅-C₁₂ aryl, C₅-C₁₂ heteroaryl, each ofwhich is optionally substituted with from one to five R²¹; or R^(a) andR^(b) together with the atoms to which they are attached form aheterocycle, and; each R²¹ is independently C₁-C₆ alkyl, C₃-C₆cycloalkyl, C₁-C₆ heteroalkyl, C₃-C₆ heterocyclic, C₅-C₁₂ aryl, C₅-C₁₂heteroaryl, or halogen; or a pharmaceutically acceptable salt thereof.2. A compound of claim 1, of Formula (Ia)

wherein R³ is C₅-C₁₀ aryl, C₅-C₁₀ heteroaryl, or C₅-C₁₀ heteroarylalkyl,each of which is optionally substituted with from 1 to 5 R²⁰ groups; or—S(O)₂NHR⁴, wherein R⁴ is C₁-C₆ alkyl or C₃-C₇ cycloalkyl, each of whichis optionally substituted with from 1 to 5 R²⁰ groups; or a moiety ofthe formula

wherein R⁶ is H, OH, or halogen; and R⁷ and R⁸ are each independentlyC₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₁-C₆heteroalkyl, C₅-C₁₂ aryl, C₅-C₁₂ heteroaryl, or C₅-C₁₂ heteroarylalkyl,each of which is optionally substituted with from 1 to 5 R²⁰ groups; orR⁶ is H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl,phenyl, naphthyl, or C₃-C₁₂ heteroaryl; and R⁷ and R⁸ together form aC₁-C₆ alkylidene group having a double bond with the carbon to whicheach of R⁶, R⁷, and R⁸ are bound wherein each of the C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, —C₃-C₆ cycloalkyl, phenyl, naphthyl, or C₃-C₁₂heteroaryl groups is optionally substituted with from 1 to 5 R²⁰ groups;Q is H, C1-C₃ alkyl, C₁-C₃ haloalkyl, benzyl or substituted benzyl; eachR²⁰ is independently C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₁-C₆ heteroalkyl,C₃-C₆ heterocyclic, C₅-C₁₂ aryl, C₅-C₁₂ heteroaryl, halogen, oxo,—OR^(a), —C(O)R^(a), —C(O)OR^(a), —C(O)NR^(a)R^(b), —OC(O)NR^(a)R^(b),—NR^(a)R^(b), —NR^(a)C(O)R^(b), —NR^(a)C(O)OR^(b), —S(O)₀₋₂R^(a),—S(O)₂R^(a)R^(b), —NR^(a)S(O)₂R^(b), —N₃, —CN, or —NO₂, wherein eachC₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₁-C₆ heteroalkyl, C₃-C₆ heterocyclic,C₅-C₁₂ aryl, C₅-C₁₂ heteroaryl is optionally substituted with from oneto five halogen, oxo, —OR^(a), —C(O)R^(a), —C(O)OR^(a),—C(O)NR^(a)R^(b), —OC(O)NR^(a)R^(b), —NR^(a)R^(b), —NR^(a)C(O)R^(b),—NR^(a)C(O)OR^(b), —S(O)₀₋₂R^(a), —S(O)₂NR^(a)R^(b), —NR^(a)S(O)₂R^(b),—N₃, —CN, or —NO₂; each R^(a) and R^(b) is independently H; or C₁-C₆alkyl, C₃-C₆ cycloalkyl, C₁-C₆ heteroalkyl, C₃-C₆ heterocyclic, C₅-C₁₂aryl, C₅-C₁₂ heteroaryl, each of which is optionally substituted withfrom one to five R²¹; or R^(a) and R^(b) together with the atoms towhich they are attached form a heterocycle, and; each R²¹ isindependently C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₃-C₆ heteroalkyl, C₃-C₆heterocyclic, C₅-C₁₂ aryl, C₅-C₁₂ heteroaryl, or halogen; or apharmaceutically acceptable salt thereof.
 3. A compound of claim 1, ofFormula (Ib)

wherein R³ is C₅-C₁₀ aryl, C₅-C₁₀ heteroaryl, or C₅-C₁₀ heteroarylalkyl,each of which is optionally substituted with from 1 to 5 R²⁰ groups; or—S(O)₂NHR⁴, wherein R is C₁-C₆ alkyl or C₃-C₇ cycloalkyl, each of whichis optionally substituted with from 1 to 5 R²⁰ groups; or a moiety ofthe formula

wherein R⁶ is H, OH, or halogen; and R⁷ and R⁸ are each independentlyC₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₁-C₆heteroalkyl, C₅-C₁₂ aryl, C₅-C₁₂ heteroaryl, or C₅-C₁₂ heteroarylalkyl,each of which is optionally substituted with from 1 to 5 R²⁰ groups; orR⁶ is H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl,phenyl, naphthyl, or C₃-C₁₂ heteroaryl; and R⁷ and R⁸ together form aC₁-C₆ alkylidene group having a double bond with the carbon to whicheach of R⁶, R⁷, and R⁸ are bound wherein each of the C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, phenyl, naphthyl, or C₃-C₁₂heteroaryl groups is optionally substituted with from 1 to 5 R²⁰ groups;each R²⁰ is independently C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₁-C₆heteroalkyl, C₃-C₆ heterocyclic, C₅-C₁₂ aryl, C₅-C₁₂ heteroaryl,halogen, oxo, —OR^(a), —C(O)R^(a), —C(O)OR^(a), —C(O)NR^(a)R^(b),—OC(O)NR^(a)R^(b), —NR^(a)R^(b), —NR^(a)C(O)R^(b), —NR^(a)C(O)OR^(b),—S(O)O₂R^(a), —S(O)₂NR^(a)R^(b), —NR^(a)S(O)₂R^(b), —N₃, —CN, or —NO₂,wherein each C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₁-C₆ heteroalkyl, C₃-C₆heterocyclic, C₅-C₁₂ aryl, C₅-C₁₂ heteroaryl is optionally substitutedwith from one to five halogen, oxo, —OR^(a), —C(O)R, —C(O)OR^(a),C(O)NR^(a)R^(b), —OC(O)NR^(a)R^(b), —NR^(a)R^(b), —NR^(a)C(O)R^(b),—NR^(a)C(O)OR^(b), —S(O)₀₋₂R^(a), —S(O)₂NR^(a)R^(b), —NR^(a)S(O)₂R^(b),—N₃, —CN, or —NO₂; each R^(a) and R^(b) is independently H; or C₁-C₆alkyl, C₃-C₆ cycloalkyl, C₁-C₆ heteroalkyl, C₃-C₆ heterocyclic, C₅-C₁₂aryl, C₅-C₁₂ heteroaryl, each of which is optionally substituted withfrom one to five R²¹; or R^(a) and R^(b) together with the atoms towhich they are attached form a heterocycle, and; each R²¹ isindependently C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₁-C₆ heteroalkyl, C₃-C₆heterocyclic, C₅-C₁₂ aryl, C₅-C₁₂ heteroaryl, or halogen; or apharmaceutically acceptable salt thereof.
 4. A compound of any of claims1-3, wherein R³ is C₅-C₁₀ aryl, C₅-C₁₀ heteroaryl, or C₅-C₁₀heteroarylalkyl, each of which is optionally substituted with from 1 to5 R²⁰ groups.
 5. A compound of any of claims 1-3, wherein R³ is a moietyof the formula

wherein R⁶ is H, OH, or halogen; and R⁷ and R⁸ are each independentlyC₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₁-C₆heteroalkyl, C₅-C₁₂ aryl, C₅-C₁₂ heteroaryl, or C₅-C₁₂ heteroarylalkyl,each of which is optionally substituted with from 1 to 5 R²⁰ groups. 6.A compound of claim 5, wherein R⁶ is OH.
 7. A compound of claim 5,wherein R⁷ and R⁸ are each independently C₁-C₆ alkyl, C₃-C₆ cycloalkyl,C₁-C₆ heteroalkyl, C₅-C₁₂ aryl, C₅-C₁₂ heteroaryl, or C₅-C₁₂heteroarylalkyl, each of which is optionally substituted with from 1 to5 R²⁰ groups.
 8. A compound of claim 5, wherein R⁷ and R⁸ are eachindependently C₁-C₆ alkyl, C₆ aryl or C₆ heteroaryl, each of which isoptionally substituted with from 1 to 5 R²⁰ groups.
 9. A compound ofclaim 5, wherein R⁷ and R⁸ are each independently C₆ aryl or C₆heteroaryl, each of which is optionally substituted with from 1 to 5 R²⁰groups.
 10. A compound of claim 5, wherein R⁷ and R⁸ are eachindependently C₁-C₆ alkyl, each of which is optionally substituted withfrom 1 to 5 R²⁰ groups.
 11. A compound chosen from the following list:


12. A compound chosen from the following list:


13. A pharmaceutical composition comprising a compound of any of claims1-12, or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier.
 14. A use of a compound of any ofclaims 1-12 for the treatment of a human having a disease or conditionresponsive to the inhibition of a bromodomain-containing protein.
 15. Ause of a compound of any of claims 1-12 for the manufacture of amedicament for the treatment of a human having a disease or conditionresponsive to the inhibition of a bromodomain-containing protein. 16.The use of any of claims 14 or 15, wherein wherein thebromodomain-containing protein is BRD4.
 17. The use of any of claims 14or 15, wherein the disease or condition is a solid tumor of the colon,rectum, prostate, lung, pancreas, liver, kidney, cervix, stomach,ovaries, breast, skin, brain, meninges, or central nervous system. 18.The use of any of claims 14 or 15, wherein the disease or condition ismultiple myeloma.
 19. The use of any of claims 14 or 15, wherein thedisease or condition is a B-cell lymphoma.
 20. The use of any of claims14 or 15, wherein the disease or condition is diffuse large B-celllymphoma or Burkitt's lymphoma.